TP53

Summary

TP53 (tumor protein p53, HGNC:11998) is a protein-coding gene on chromosome 17p13.1, encoding Cellular tumor antigen p53 (P04637). Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence. In precision oncology, TP53 Deleterious Mutation confers sensitivity to Adjuvant Chemotherapy in Lung Non-small Cell Carcinoma (CIViC Level B); 72 further curated variant–drug associations are listed below. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277).

Source: NCBI Gene 7157 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Li-Fraumeni syndrome (Definitive, ClinGen) — +7 more curated relationships
• GWAS associations: 50
• Clinical variants (ClinVar): 3,923 total — 771 pathogenic, 198 likely-pathogenic
• Phenotypes (HPO): 224
• Druggable target: yes — 196 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 73 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 74 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 1,043 downstream targets (CollecTRI)
• MANE Select transcript: NM_000546

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11998
Approved symbol	TP53
Name	tumor protein p53
Location	17p13.1
Locus type	gene with protein product
Status	Approved
Aliases	p53, LFS1
Ensembl gene	ENSG00000141510
Ensembl biotype	protein_coding
OMIM	191170
Entrez	7157

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 34 protein_coding, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000269305, ENST00000359597, ENST00000413465, ENST00000420246, ENST00000445888, ENST00000455263, ENST00000503591, ENST00000504290, ENST00000504937, ENST00000505014, ENST00000508793, ENST00000509690, ENST00000510385, ENST00000514944, ENST00000571370, ENST00000574684, ENST00000576024, ENST00000604348, ENST00000610292, ENST00000610538, ENST00000610623, ENST00000618944, ENST00000619186, ENST00000619485, ENST00000620739, ENST00000622645, ENST00000635293, ENST00000714356, ENST00000714357, ENST00000714358, ENST00000714359, ENST00000714408, ENST00000714409, ENST00000905353, ENST00000923566, ENST00000923567, ENST00000923568, ENST00000923569, ENST00000949117

RefSeq mRNA: 25 — MANE Select: NM_000546 NM_000546, NM_001126112, NM_001126113, NM_001126114, NM_001126115, NM_001126116, NM_001126117, NM_001126118, NM_001276695, NM_001276696, NM_001276697, NM_001276698, NM_001276699, NM_001276760, NM_001276761, NM_001407262, NM_001407263, NM_001407264, NM_001407265, NM_001407266, NM_001407267, NM_001407268, NM_001407269, NM_001407270, NM_001407271

CCDS: CCDS11118, CCDS45605, CCDS45606, CCDS73963, CCDS73964, CCDS73965, CCDS73966, CCDS73967, CCDS73968, CCDS73969, CCDS73970, CCDS73971

Canonical transcript exons

ENST00000269305 — 11 exons

Exon	Start	End
ENSE00002419584	7676382	7676403
ENSE00003518480	7675053	7675236
ENSE00003545950	7670609	7670715
ENSE00003625790	7675994	7676272
ENSE00003712342	7674181	7674290
ENSE00003723991	7674859	7674971
ENSE00003725258	7673701	7673837
ENSE00003753508	7687377	7687490
ENSE00003786593	7673535	7673608
ENSE00004023724	7668421	7669690
ENSE00004023728	7676521	7676622

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 95.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 53.5633 / max 319.9960, expressed in 1811 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
164278	52.9906	1811
164274	0.3814	188
164273	0.1219	46
164275	0.0693	33

Top tissues by expression

281 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	95.11	gold quality
ganglionic eminence	UBERON:0004023	94.13	gold quality
tendon of biceps brachii	UBERON:0008188	92.63	gold quality
monocyte	CL:0000576	90.86	gold quality
stromal cell of endometrium	CL:0002255	90.85	gold quality
leukocyte	CL:0000738	90.78	gold quality
mononuclear cell	CL:0000842	90.55	gold quality
skin of abdomen	UBERON:0001416	90.47	gold quality
rectum	UBERON:0001052	90.40	gold quality
granulocyte	CL:0000094	90.35	gold quality
skin of leg	UBERON:0001511	90.30	gold quality
smooth muscle tissue	UBERON:0001135	90.23	gold quality
mucosa of transverse colon	UBERON:0004991	90.20	gold quality
embryo	UBERON:0000922	90.05	gold quality
sural nerve	UBERON:0015488	89.63	gold quality
right ovary	UBERON:0002118	89.59	gold quality
left ovary	UBERON:0002119	89.12	gold quality
esophagus mucosa	UBERON:0002469	88.83	gold quality
colonic epithelium	UBERON:0000397	88.70	gold quality
zone of skin	UBERON:0000014	88.47	gold quality
left uterine tube	UBERON:0001303	88.31	gold quality
vermiform appendix	UBERON:0001154	88.27	gold quality
right coronary artery	UBERON:0001625	88.24	gold quality
spleen	UBERON:0002106	88.22	gold quality
ovary	UBERON:0000992	88.01	gold quality
lymph node	UBERON:0000029	87.97	gold quality
ectocervix	UBERON:0012249	87.88	gold quality
vagina	UBERON:0000996	87.72	gold quality
body of uterus	UBERON:0009853	87.70	gold quality
transverse colon	UBERON:0001157	87.60	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.27
E-MTAB-9801	yes	5.97
E-ENAD-17	no	167.86

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1043 targets.

Target	Regulation
AAR2
ABCB1	Repression
ABCC1	Activation
ABCC2	Activation
ABCC3	Activation
ABCC4	Activation
ABCG2	Unknown
ABI3BP	Unknown
ABL1
ABL2
ACHE
ACTA1
ACTA2	Unknown
ACTL6A
ADA	Unknown
ADAM2
ADAMTSL1	Activation
ADARB1
ADCYAP1R1	Activation
ADGRB1	Unknown
ADGRB2	Unknown
ADIPOQ
ADRA1D
AFP	Repression
AGA
AIFM1	Activation
AIFM2	Activation
AKR1B10	Repression
AKT1	Repression
AKT2

JASPAR motifs

Motif	Name	Family
MA0106.1	TP53	p53-related factors
MA0106.2	TP53	p53-related factors
MA0106.3	TP53	p53-related factors

JASPAR matrix evidence (PMIDs): PMID:1588974

Upstream regulators (CollecTRI, top): AATF, ABL1, AHR, AP1, AR, ATF3, BACH2, BCL6, BCLAF1, BDP1, BHLHE40, BMAL1, CASZ1, CEBPB, CELF1, CREB1, CREBBP, CTCF, DNMT1, DRAM2, E2F1, E2F2, EGR1, EIF5A, ELF4, ERCC2, ESR1, ETS1, ETS2, EZH2, FOS, FOXC1, FOXM1, FOXN1, FOXO1, FOXO3, GATA2, GATA4, GFI1, GLI1

miRNA regulators (miRDB)

58 targeting TP53, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-6731-5P	99.28	67.42	2375

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• There was a differential upregulation of p53-responsive genes by genotoxic stress in hematopoietic cells containing wild-type p53 (MOLT-4) or a mutant p53 with a codon 161 mutation (U266). (PMID:10794522)
• Binding to the p53 binding sites of the Mdm2 promoter alleviates the requirement for p53 C-terminal activation. (PMID:11328884)
• P72R polymorphism in human papillomavirus associated premalignant laryngeal neoplasm (PMID:11403041)
• phosphorylation of p53 was rapidly induced in human fibroblasts upon exposure of cells to hydrogen peroxide (H(2)O(2)) (PMID:11447225)
• A loss of wild-type p53 gene function and consequent p53 overexpression in gastric carcinomas may be involved in early stages of tumor progression. (PMID:11518545)
• protein stability measured by hydrogen exchange (PMID:11559355)
• Restoration of wt-p53 activity in Hep3B leads to sensitiveness to chemotherapeutic agents because of the decrease of p-glycoprotein expression. (PMID:11602059)
• differentiation status of the tumor was found for the p53 aberration but not for CD95 expression. (PMID:11692157)
• No association was found between the p53 codon 72 polymorphism and rheumatoid arthritis. (PMID:11708408)
• interactions with DNA in solution using time lapse atomic force microscopy (PMID:11718557)
• Mutations of p53 gene were present in 24% (5 of 21) of the evaluable cases, all of them overexpressing p53 in the majority of tumor cells. (PMID:11733360)
• Tissue samples from 42 ulcerative colitis patients were evaluated for p53 alterations by immunohistochemistry, loss of heterozygosity analysis, polymerase chain reaction-single-strand conformation polymorphism and direct sequencing. (PMID:11737306)
• WOX1/p53 has a potential role as a signaling complex in mitochondrial apoptosis. (PMID:11744990)
• different genotype combinations of p53 and GSTM1 increase the risk of developing specific histological subtypes of NSCLC. (PMID:11751390)
• DNA-PK and p53 may form a sensor complex that detects the disruption of DNA replication caused by nucleoside analogue incorporation and may subsequently signal for apoptosis. (PMID:11751391)
• Expression of Id helix-loop-helix proteins in colorectal adenocarcinoma correlates with p53 expression and mitotic index. (PMID:11751402)
• We show a novel alternative pathway of apoptosis in human primary cells that is mediated by transcriptionally dependent decreases in p53 and c-Myc and decreases in p21. (PMID:11751853)
• pH-sensitive molecular defect of p53 (R337H)suggests that pH-dependent p53 dysfunction is the molecular basis for cases of adrenocortical carcinoma in Brazilian children (PMID:11753428)
• New mutations of p53 identified by SSCP in acute myeloid leukemia cell lines. Loss of p53 is not the decisive event causing tumor cells to proliferate in vitro without externally added growth factors. (PMID:11755471)
• To determine whether genotoxic stress regulates DNA binding by p53 in vivo, we have performed quantitative chromatin immunoprecipitation (ChIP) assays on tumor and normal cell lines containing wild-type p53 (PMID:11756653)
• A lower invasiveness and shorter survival was seen in tumors with a TP53 mutation (PMID:11763417)
• higher expression in childhood leukemias with poor prognosis compared to long-term survivors (PMID:11764099)
• Mutation pattern included base substitution (point mutation, G–>T, T–>G) and frame-shift mutation (base insertion and base loss). (PMID:11776898)
• acetylation of p53 activates transcription through recruitment of coactivators/histone acetyltransferases (PMID:11779500)
• role in inducing CD95 gene expression in endothelial cells exposed to doxorubicin (PMID:11779855)
• P53 protein overexpression is an early event in esophageal carcinogenesis and useful biomarkers for early detection. (PMID:11783017)
• P53 protein expression and intratumoral microvessel density (IMVD) can be considered as a biological indicator of malignant potential in brain astrocytoma. (PMID:11783119)
• These results demonstrate that butyrate inhibited the growth of breast cancer cells in a P53-independent manner. (PMID:11786482)
• protein inhibitor of activated Stat1 (PIAS1) interacts with the tetramerization and C-terminal regulatory domains of p53 in yeast two-hybrid analyses (PMID:11788578)
• Telomerase activity in microdissected human breast cancer tissues: association with p53, p21 and outcome (PMID:11788906)
• TP53-mutated tumors need fewer additional genetic alterations to develop metastases in primary head and neck tumors compared with TP53 wild-type primary tumors. (PMID:11793443)
• systematic automated analysis of the effects of p53 mutations on the structure of the core domain of the protein (PMID:11793474)
• IkappaBalpha x p53 complex plays an important role in responses involving growth regulation, apoptosis, and hypoxic stress (PMID:11799106)
• These results suggest that p53 might modulate the repair of DNA adducts generated from the human bladder carcinogen ABP in its target human uroepithelial cells. (PMID:11804609)
• nuclear mutant p53 protein is expressed in early precancerous stages suggesting this is an early change in NSCLC tumorigenesis; may be a potential marker for development of NSCLC (PMID:11804688)
• biogenesis in vitro to determine how wild type and mutant forms form hetero-oligomers (PMID:11805092)
• Polymorphism at p53 codon 72: A striking reduction in Pro/Pro allele frequency has been found in HPV positive cases, indicating Arg/Arg genotype to be more susceptible to HPV infection and oral carcinogenesis (PMID:11807792)
• p53, activated by NF-kappa B, is essential for H(2)O(2)-induced apoptosis in glioma cells (PMID:11809417)
• Repression of hepatocyte nuclear factor 4alpha tumor suppressor p53: involvement of the ligand-binding domain and histone deacetylase activity (PMID:11818510)
• p53 expression was an independent parameter related to a poor prognosis in diffuse large B cell non-Hodgkin’s lymphomas. (PMID:11818669)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tp53	ENSDARG00000035559
mus_musculus	Trp53	ENSMUSG00000059552
rattus_norvegicus	Tp53	ENSRNOG00000010756
drosophila_melanogaster	p53	FBGN0039044

Paralogs (2): TP63 (ENSG00000073282), TP73 (ENSG00000078900)

Protein

Protein identifiers

Cellular tumor antigen p53 — P04637 (reviewed: P04637)

Alternative names: Antigen NY-CO-13, Phosphoprotein p53, Tumor suppressor p53

All UniProt accessions (19): A0A087WT22, A0A087WXZ1, A0A087X1Q1, A0A0U1RQC9, A0A386NBZ1, A0AAQ5BHX5, A0AAQ5BHY1, A0AAQ5BHZ9, E7EMR6, P04637, E7EQX7, E7ESS1, E9PCY9, E9PFT5, H2EHT1, I3L0W9, J3KP33, K7PPA8, S4R334

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence. Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type. Negatively regulates cell division by controlling expression of a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. Its pro-apoptotic activity is activated via its interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2. However, this activity is inhibited when the interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 is displaced by PPP1R13L/iASPP. In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; the function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seems to have an effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis. Regulates the circadian clock by repressing CLOCK-BMAL1-mediated transcriptional activation of PER2.

Subunit / interactions. Forms homodimers and homotetramers. Binds DNA as a homotetramer. Interacts with AXIN1. Probably part of a complex consisting of TP53, HIPK2 and AXIN1. Interacts with histone acetyltransferases EP300 and methyltransferases HRMT1L2 and CARM1, and recruits them to promoters. Interacts (via C-terminus) with TAF1; when TAF1 is part of the TFIID complex. Interacts with ING4; this interaction may be indirect. Found in a complex with CABLES1 and TP73. Interacts with HIPK1, HIPK2, and TP53INP1. Interacts with WWOX. May interact with HCV core protein. Interacts with USP7 and SYVN1. Interacts with HSP90AB1. Interacts with CHD8; leading to recruit histone H1 and prevent transactivation activity. Interacts with ARMC10, CDKN2AIP, NUAK1, STK11/LKB1, UHRF2 and E4F1. Interacts with YWHAZ; the interaction enhances TP53 transcriptional activity. Phosphorylation of YWHAZ on ‘Ser-58’ inhibits this interaction. Interacts (via DNA-binding domain) with MAML1 (via N-terminus). Interacts with MKRN1. Interacts with PML (via C-terminus). Interacts with MDM2; leading to ubiquitination and proteasomal degradation of TP53. Directly interacts with FBXO42; leading to ubiquitination and degradation of TP53. Interacts (phosphorylated at Ser-15 by ATM) with the phosphatase PP2A-PPP2R5C holoenzyme; regulates stress-induced TP53-dependent inhibition of cell proliferation. Interacts with PPP2R2A. Interacts with AURKA, DAXX, BRD7 and TRIM24. Interacts (when monomethylated at Lys-382) with L3MBTL1. Isoform 1 interacts with isoform 2 and with isoform 4. Interacts with GRK5. Binds to the CAK complex (CDK7, cyclin H and MAT1) in response to DNA damage. Interacts with CDK5 in neurons. Interacts with AURKB, SETD2, UHRF2 and NOC2L. Interacts (via N-terminus) with PTK2/FAK1; this promotes ubiquitination by MDM2. Interacts with PTK2B/PYK2; this promotes ubiquitination by MDM2. Interacts with PRKCG. Interacts with PPIF; the association implicates preferentially tetrameric TP53, is induced by oxidative stress and is impaired by cyclosporin A (CsA). Interacts with SNAI1; the interaction induces SNAI1 degradation via MDM2-mediated ubiquitination and inhibits SNAI1-induced cell invasion. Interacts with UBC9. Interacts with ZNF385B; the interaction is direct. Interacts (via DNA-binding domain) with ZNF385A; the interaction is direct and enhances p53/TP53 transactivation functions on cell-cycle arrest target genes, resulting in growth arrest. Interacts with ANKRD2. Interacts with RFFL and RNF34; involved in p53/TP53 ubiquitination. Interacts with MTA1 and COP1. Interacts with CCAR2 (via N-terminus). Interacts with MORC3. Interacts (via C-terminus) with POU4F2 isoform 1 (via C-terminus). Interacts (via oligomerization region) with NOP53; the interaction is direct and may prevent the MDM2-mediated proteasomal degradation of TP53. Interacts with AFG1L; mediates mitochondrial translocation of TP53. Interacts with UBD. Interacts with TAF6 isoform 1 and isoform 4. Interacts with C10orf90/FATS; the interaction inhibits binding of TP53 and MDM2. Interacts with NUPR1; interaction is stress-dependent. Forms a complex with EP300 and NUPR1; this complex binds CDKN1A promoter leading to transcriptional induction of CDKN1A. Interacts with PRMT5 in response to DNA damage; the interaction is TTC5/STRAP dependent. Interacts with PPP1R13L (via SH3 domain and ANK repeats); the interaction inhibits pro-apoptotic activity of p53/TP53. Interacts with PPP1R13B/ASPP1 and TP53BP2/ASPP2; the interactions promotes pro-apoptotic activity. When phosphorylated at Ser-15, interacts with DDX3X and gamma-tubulin. Interacts with KAT7/HBO1; leading to inhibit histone acetyltransferase activity of KAT7/HBO1. Interacts (via N-terminus) with E3 ubiquitin-protein ligase MUL1; the interaction results in ubiquitination of cytoplasmic TP53 at Lys-24 and subsequent proteasomal degradation. Interacts with S100A4; this interaction promotes TP53 degradation. Interacts with BANP. Interacts with TTC5/STRAP; the interaction may result in increased mitochondrial-dependent apoptosis. Interacts with NQO1; this interaction is NADH-dependent, stabilizes TP53 in response to oxidative stress and protects it from ubiquitin-independent degradation by the 20S proteasome. Interacts with DAZAP2 at TP53 target gene promoters; the interaction is triggered by DNA damage and leads to modulation of the expression of a subset of TP53 target genes, reducing DNA damage-induced cell death by limiting the expression of cell death-mediating TP53 target genes. Interacts (via N-terminus) with ZNF768 (via zinc-finger domains); interaction might be facilitated by TP53 oligomerization state. Forms a ternary complex with ALDOB and G6PD; this interaction is direct. ALDOB stabilizes the complex inhibiting G6PD activity and keeping oxidative pentose phosphate metabolism in check. Interacts with MORN3; the interactions mediate post-transcriptional modifications of TP53 by MDM2 and SIRT1. Interacts with HSPA9/MOT-2; the interaction promotes the degradation of TP53. Interacts with FBXO22; this interaction promotes TP53 proteasomal degradation. (Microbial infection) Interacts with cancer-associated/HPV E6 viral proteins leading to ubiquitination and degradation of TP53 giving a possible model for cell growth regulation. This complex formation requires an additional factor, E6-AP, which stably associates with TP53 in the presence of E6. (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL123. (Microbial infection) Interacts (via N-terminus) with human adenovirus 5 E1B-55K protein; this interaction leads to the inhibition of TP53 function and/or its degradation. (Microbial infection) Interacts with Kaposi’s sarcoma-associated herpesvirus/HHV-8 protein ORF45; this interaction results in the cytoplasmic localization of TP53 thereby decreasing its transcriptional activity.

Subcellular location. Cytoplasm. Nucleus. PML body. Endoplasmic reticulum. Mitochondrion matrix. Cytoskeleton. Microtubule organizing center. Centrosome Nucleus. Cytoplasm Nucleus. Cytoplasm Cytoplasm.

Tissue specificity. Ubiquitous. Isoforms are expressed in a wide range of normal tissues but in a tissue-dependent manner. Isoform 2 is expressed in most normal tissues but is not detected in brain, lung, prostate, muscle, fetal brain, spinal cord and fetal liver. Isoform 3 is expressed in most normal tissues but is not detected in lung, spleen, testis, fetal brain, spinal cord and fetal liver. Isoform 7 is expressed in most normal tissues but is not detected in prostate, uterus, skeletal muscle and breast. Isoform 8 is detected only in colon, bone marrow, testis, fetal brain and intestine. Isoform 9 is expressed in most normal tissues but is not detected in brain, heart, lung, fetal liver, salivary gland, breast or intestine.

Post-translational modifications. Acetylation of Lys-382 by CREBBP enhances transcriptional activity. Acetylation of Lys-382 by EP300. Deacetylation of Lys-382 by SIRT1 impairs its ability to induce proapoptotic program and modulate cell senescence. Deacetylation by SIRT2 impairs its ability to induce transcription activation in a AKT-dependent manner. Acetylation at Lys-381 increases stability. Deacetylation at Lys-381 by SIRT6 decreases its stability, thereby regulating cell senescence. Acetylated at Lys-120 by KAT5, KAT6A and KAT8; regulating its ability to induce proapoptotic program. Lactylation by AARS1 prevents ability to undergo liquid-liquid phase separation (LLPS), thereby inhibiting transcription factor activity. Phosphorylation on Ser residues mediates transcriptional activation. Phosphorylated by HIPK1. Phosphorylation at Ser-9 by HIPK4 increases repression activity on BIRC5 promoter. Phosphorylated on Thr-18 by VRK1, which may prevent the interaction with MDM2. Phosphorylated on Ser-20 by CHEK2 in response to DNA damage, which prevents ubiquitination by MDM2. Phosphorylated on Ser-20 by PLK3 in response to reactive oxygen species (ROS), promoting p53/TP53-mediated apoptosis. Phosphorylated on Thr-55 by TAF1, which promotes MDM2-mediated degradation. Phosphorylated on Ser-33 by CDK7 in a CAK complex in response to DNA damage. Phosphorylated on Ser-46 by HIPK2 upon UV irradiation. Phosphorylation on Ser-46 is required for acetylation by CREBBP. Phosphorylated on Ser-392 following UV but not gamma irradiation. Phosphorylated by NUAK1 at Ser-15 and Ser-392; was initially thought to be mediated by STK11/LKB1 but it was later shown that it is indirect and that STK11/LKB1-dependent phosphorylation is probably mediated by downstream NUAK1. It is unclear whether AMP directly mediates phosphorylation at Ser-15. Phosphorylated on Thr-18 by isoform 1 and isoform 2 of VRK2. Phosphorylation on Thr-18 by isoform 2 of VRK2 results in a reduction in ubiquitination by MDM2 and an increase in acetylation by EP300. Stabilized by CDK5-mediated phosphorylation in response to genotoxic and oxidative stresses at Ser-15, Ser-33 and Ser-46, leading to accumulation of p53/TP53, particularly in the nucleus, thus inducing the transactivation of p53/TP53 target genes. Phosphorylated by DYRK2 at Ser-46 in response to genotoxic stress. Phosphorylated at Ser-315 and Ser-392 by CDK2 in response to DNA-damage. Phosphorylation at Ser-15 is required for interaction with DDX3X and gamma-tubulin. Phosphorylation at Ser-392 regulates its ability to undergo liquid-liquid phase separation by increasing fluidity of TP53/p53 condensates. Dephosphorylated by PP2A-PPP2R5C holoenzyme at Thr-55. SV40 small T antigen inhibits the dephosphorylation by the AC form of PP2A. May be O-glycosylated in the C-terminal basic region. Studied in EB-1 cell line. Ubiquitinated by MDM2 and SYVN1, which leads to proteasomal degradation. Ubiquitinated by RFWD3, which works in cooperation with MDM2 and may catalyze the formation of short polyubiquitin chains on p53/TP53 that are not targeted to the proteasome. Ubiquitinated by MKRN1 at Lys-291 and Lys-292, which leads to proteasomal degradation. Deubiquitinated by USP10, leading to its stabilization. Ubiquitinated by TRIM24, RFFL, RNF34 and RNF125, which leads to proteasomal degradation. Ubiquitination by TOPORS induces degradation. Deubiquitination by USP7, leading to stabilization. Isoform 4 is monoubiquitinated in an MDM2-independent manner. Ubiquitinated by COP1, which leads to proteasomal degradation. Ubiquitination and subsequent proteasomal degradation is negatively regulated by CCAR2. Polyubiquitinated by C10orf90/FATS, polyubiquitination is ‘Lys-48’-linkage independent and non-proteolytic, leading to TP53 stabilization. Polyubiquitinated by MUL1 at Lys-24 which leads to proteasomal degradation. Deubiquitinated by USP3, leading to stabilization. Ubiquitinated by MSL2, promoting its cytoplasmic localization. Also ubiquitinated by the SCF(FBXO22)-KDMA4A complex; leading to proteasomal degradation. Monomethylated at Lys-372 by SETD7, leading to stabilization and increased transcriptional activation. Monomethylated at Lys-370 by SMYD2, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity. Lys-372 monomethylation prevents interaction with SMYD2 and subsequent monomethylation at Lys-370. Dimethylated at Lys-373 by EHMT1 and EHMT2. Monomethylated at Lys-382 by KMT5A, promoting interaction with L3MBTL1 and leading to repress transcriptional activity. Dimethylation at Lys-370 and Lys-382 diminishes p53 ubiquitination, through stabilizing association with the methyl reader PHF20. Demethylation of dimethylated Lys-370 by KDM1A prevents interaction with TP53BP1 and represses TP53-mediated transcriptional activation. Monomethylated at Arg-333 and dimethylated at Arg-335 and Arg-337 by PRMT5; methylation is increased after DNA damage and might possibly affect TP53 target gene specificity. Sumoylated with SUMO1. Sumoylated at Lys-386 by UBC9.

Disease relevance. TP53 is found in increased amounts in a wide variety of transformed cells. TP53 is frequently mutated or inactivated in about 60% of cancers. TP53 defects are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium. The condition develops as a complication in approximately 10% of patients with chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma. Esophageal cancer (ESCR) [MIM:133239] A malignancy of the esophagus. The most common types are esophageal squamous cell carcinoma and adenocarcinoma. Cancer of the esophagus remains a devastating disease because it is usually not detected until it has progressed to an advanced incurable stage. The disease is caused by variants affecting the gene represented in this entry. Li-Fraumeni syndrome (LFS) [MIM:151623] An autosomal dominant familial cancer syndrome that in its classic form is defined by the existence of a proband affected by a sarcoma before 45 years with a first degree relative affected by any tumor before 45 years and another first degree relative with any tumor before 45 years or a sarcoma at any age. Other clinical definitions for LFS have been proposed and called Li-Fraumeni like syndrome (LFL). In these families affected relatives develop a diverse set of malignancies at unusually early ages. Four types of cancers account for 80% of tumors occurring in TP53 germline mutation carriers: breast cancers, soft tissue and bone sarcomas, brain tumors (astrocytomas) and adrenocortical carcinomas. Less frequent tumors include choroid plexus carcinoma or papilloma before the age of 15, rhabdomyosarcoma before the age of 5, leukemia, Wilms tumor, malignant phyllodes tumor, colorectal and gastric cancers. The disease is caused by variants affecting the gene represented in this entry. Squamous cell carcinoma of the head and neck (HNSCC) [MIM:275355] A non-melanoma skin cancer affecting the head and neck. The hallmark of cutaneous SCC is malignant transformation of normal epidermal keratinocytes. The gene represented in this entry is involved in disease pathogenesis. Lung cancer (LNCR) [MIM:211980] A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. The disease is caused by variants affecting the gene represented in this entry. Papilloma of choroid plexus (CPP) [MIM:260500] A benign tumor of neuroectodermal origin that generally occurs in childhood, but has also been reported in adults. Although generally found within the ventricular system, choroid plexus papillomas can arise ectopically in the brain parenchyma or disseminate throughout the neuraxis. Patients present with signs and symptoms of increased intracranial pressure including headache, hydrocephalus, papilledema, nausea, vomiting, cranial nerve deficits, gait impairment, and seizures. The disease is caused by variants affecting the gene represented in this entry. Adrenocortical carcinoma (ADCC) [MIM:202300] A malignant neoplasm of the adrenal cortex and a rare childhood tumor. It occurs with increased frequency in patients with Beckwith-Wiedemann syndrome and Li-Fraumeni syndrome. The disease is caused by variants affecting the gene represented in this entry. Basal cell carcinoma 7 (BCC7) [MIM:614740] A common malignant skin neoplasm that typically appears on hair-bearing skin, most commonly on sun-exposed areas. It is slow growing and rarely metastasizes, but has potentialities for local invasion and destruction. It usually develops as a flat, firm, pale area that is small, raised, pink or red, translucent, shiny, and waxy, and the area may bleed following minor injury. Tumor size can vary from a few millimeters to several centimeters in diameter. Disease susceptibility is associated with variants affecting the gene represented in this entry. Bone marrow failure syndrome 5 (BMFS5) [MIM:618165] A form of bone marrow failure syndrome, a heterogeneous group of life-threatening disorders characterized by hematopoietic defects in association with a range of variable extra-hematopoietic manifestations. BMFS5 is an autosomal dominant form characterized by infantile onset of severe red cell anemia requiring transfusion. Additional features include hypogammaglobulinemia, poor growth with microcephaly, developmental delay, and seizures. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. The N-terminal and C-terminal disordered regions undergo liquid-liquid phase separation (LLPS) following homotetramerization and activation. Post-translational modifications, such as phosphorylation or lactylation affect the ability to undergo LLPS. The nuclear export signal acts as a transcriptional repression domain. The TADI and TADII motifs (residues 17 to 25 and 48 to 56) correspond both to 9aaTAD motifs which are transactivation domains present in a large number of yeast and animal transcription factors.

Induction. Up-regulated in response to DNA damage. Isoform 2 is not induced in tumor cells in response to stress.

Miscellaneous. Expressed in quiescent lymphocytes. Seems to be non-functional. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. Expressed in quiescent lymphocytes. Seems to be non-functional. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. Produced by alternative promoter usage. Produced by alternative promoter usage and alternative splicing. Produced by alternative promoter usage and alternative splicing.

Similarity. Belongs to the p53 family.

Isoforms (9)

UniProt ID	Names	Canonical?
P04637-1	1, p53, p53alpha	yes
P04637-2	2, I9RET, p53beta
P04637-3	3, p53gamma
P04637-4	4, Del40-p53, Del40-p53alpha, p47
P04637-5	5, Del40-p53beta
P04637-6	6, Del40-p53gamma
P04637-7	7, Del133-p53, Del133-p53alpha
P04637-8	8, Del133-p53beta
P04637-9	9, Del133-p53gamma

RefSeq proteins (25): NP_000537, NP_001119584, NP_001119585, NP_001119586, NP_001119587, NP_001119588, NP_001119589, NP_001119590, NP_001263624, NP_001263625, NP_001263626, NP_001263627, NP_001263628, NP_001263689, NP_001263690, NP_001394191, NP_001394192, NP_001394193, NP_001394194, NP_001394195, NP_001394196, NP_001394197, NP_001394198, NP_001394199, NP_001394200 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002117	p53_tumour_suppressor	Family
IPR008967	p53-like_TF_DNA-bd_sf	Homologous_superfamily
IPR010991	p53_tetrameristn	Domain
IPR011615	p53_DNA-bd	Domain
IPR012346	p53/RUNT-type_TF_DNA-bd_sf	Homologous_superfamily
IPR013872	p53_transactivation_domain	Domain
IPR036674	p53_tetramer_sf	Homologous_superfamily
IPR040926	p53_TAD2	Domain
IPR057064	P53_central_site	Conserved_site

Pfam: PF00870, PF07710, PF08563, PF18521

UniProt features (1518 total): sequence variant 1363, mutagenesis site 38, modified residue 30, region of interest 20, strand 19, helix 14, turn 7, cross-link 6, splice variant 6, short sequence motif 5, binding site 4, compositionally biased region 3, chain 1, DNA-binding region 1, site 1

Structure

Experimental structures (PDB)

313 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9C5S	X-RAY DIFFRACTION	1.01
3D06	X-RAY DIFFRACTION	1.2
5MHC	X-RAY DIFFRACTION	1.2
8UQR	X-RAY DIFFRACTION	1.22
6GGC	X-RAY DIFFRACTION	1.24
6SHZ	X-RAY DIFFRACTION	1.24
4MZI	X-RAY DIFFRACTION	1.25
6GGE	X-RAY DIFFRACTION	1.25
3LW1	X-RAY DIFFRACTION	1.28
5O1E	X-RAY DIFFRACTION	1.3
6RL3	X-RAY DIFFRACTION	1.3
8E7A	X-RAY DIFFRACTION	1.3
5O1C	X-RAY DIFFRACTION	1.32
5O1H	X-RAY DIFFRACTION	1.32
6GGB	X-RAY DIFFRACTION	1.32
6GGF	X-RAY DIFFRACTION	1.32
7B4N	X-RAY DIFFRACTION	1.32
3ZME	X-RAY DIFFRACTION	1.35
5AOK	X-RAY DIFFRACTION	1.35
5G4N	X-RAY DIFFRACTION	1.35
5O1G	X-RAY DIFFRACTION	1.35
6V4F	X-RAY DIFFRACTION	1.35
5AB9	X-RAY DIFFRACTION	1.36
5O1D	X-RAY DIFFRACTION	1.36
8A92	X-RAY DIFFRACTION	1.37
5G4M	X-RAY DIFFRACTION	1.38
5O1F	X-RAY DIFFRACTION	1.38
8QWO	X-RAY DIFFRACTION	1.38
9S9L	X-RAY DIFFRACTION	1.38
7B4H	X-RAY DIFFRACTION	1.39

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04637-F1	75.83	0.54

Antibody-complex structures (SAbDab): 2 — 4QO1, 6W51

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 120 (interaction with dna)

Ligand- & substrate-binding residues (4): 176; 179; 238; 242

Post-translational modifications (36): 9, 15, 18, 20, 33, 37, 46, 55, 120, 120, 139, 183, 269, 284, 305, 315, 321, 333, 335, 337 …

Mutagenesis-validated functional residues (38):

Position	Phenotype
15	loss of interaction with ppp2r5c, ppp2ca and ppp2r1a.
18	no effect on interaction with mdm2 and increase in protein levels after dna damage.
20	abolishes phosphorylation site. abolishes increase in protein levels after dna damage.
20	constitutively increased tp53 protein levels.
22–23	loss of interaction with mdm2, leading to constitutively increased tp53 protein levels.
24	abolishes ubiquitination by mul1.
37	abolishes phosphorylation by mapkapk5.
46	abolishes phosphorylation by dyrk2 and hipk2 and acetylation of k-382 by crebbp.
46	alters interaction with wwox.
55	blocks phosphorylation by taf1.
183	abolishes strongly phosphorylation.
183	inhibits slightly its transcriptional activity.
248	does not induce snai1 degradation.
269	abolishes phosphorylation.
269	inhibits strongly its transcriptional activity.
284	inhibits strongly its transcriptional activity.
291–292	abolishes polyubiquitination by mkrn1.
319	loss of nuclear localization; when associated with a-320 and a-321.
320	loss of nuclear localization; when associated with a-319 and a-321.
321	loss of nuclear localization; when associated with a-319 and a-320.
333–337	reduced methylation by prmt5. reduced nuclear localization. decreased binding to promoters of target genes. reduced tran
359	abolishes binding to usp7.
361	abolishes binding to usp7.
362	abolishes binding to usp7.
370	induces a decrease in methylation by smyd2.

Function

Pathways and Gene Ontology

Reactome pathways

46 pathways

ID	Pathway
R-HSA-111448	Activation of NOXA and translocation to mitochondria
R-HSA-139915	Activation of PUMA and translocation to mitochondria
R-HSA-1912408	Pre-NOTCH Transcription and Translation
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-2559584	Formation of Senescence-Associated Heterochromatin Foci (SAHF)
R-HSA-2559585	Oncogene Induced Senescence
R-HSA-2559586	DNA Damage/Telomere Stress Induced Senescence
R-HSA-3232118	SUMOylation of transcription factors
R-HSA-349425	Autodegradation of the E3 ubiquitin ligase COP1
R-HSA-390471	Association of TriC/CCT with target proteins during biosynthesis
R-HSA-5620971	Pyroptosis
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-5689880	Ub-specific processing proteases
R-HSA-5689896	Ovarian tumor domain proteases
R-HSA-5693565	Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-6796648	TP53 Regulates Transcription of DNA Repair Genes
R-HSA-6803204	TP53 Regulates Transcription of Genes Involved in Cytochrome C Release
R-HSA-6803205	TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain
R-HSA-6803207	TP53 Regulates Transcription of Caspase Activators and Caspases
R-HSA-6803211	TP53 Regulates Transcription of Death Receptors and Ligands
R-HSA-6804114	TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest
R-HSA-6804115	TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain
R-HSA-6804116	TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest
R-HSA-6804754	Regulation of TP53 Expression
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation
R-HSA-6804757	Regulation of TP53 Degradation
R-HSA-6804758	Regulation of TP53 Activity through Acetylation
R-HSA-6804759	Regulation of TP53 Activity through Association with Co-factors
R-HSA-6804760	Regulation of TP53 Activity through Methylation

MSigDB gene sets: 1239 (showing top): GOBP_CIRCADIAN_RHYTHM, GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, CREL_01, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, REACTOME_SIGNALING_BY_NOTCH, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_POSITIVE_REGULATION_OF_LYMPHOCYTE_APOPTOTIC_PROCESS, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE_BY_P53_CLASS_MEDIATOR, REACTOME_INNATE_IMMUNE_SYSTEM, BIOCARTA_TEL_PATHWAY, GOBP_BEHAVIOR, GOBP_NEGATIVE_REGULATION_OF_TELOMERE_MAINTENANCE_VIA_TELOMERASE

GO Biological Process (144): negative regulation of transcription by RNA polymerase II (GO:0000122), mitophagy (GO:0000423), in utero embryonic development (GO:0001701), somitogenesis (GO:0001756), release of cytochrome c from mitochondria (GO:0001836), hematopoietic progenitor cell differentiation (GO:0002244), T cell proliferation involved in immune response (GO:0002309), B cell lineage commitment (GO:0002326), T cell lineage commitment (GO:0002360), response to ischemia (GO:0002931), nucleotide-excision repair (GO:0006289), double-strand break repair (GO:0006302), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), protein import into nucleus (GO:0006606), autophagy (GO:0006914), DNA damage response (GO:0006974), ER overload response (GO:0006983), transforming growth factor beta receptor signaling pathway (GO:0007179), Ras protein signal transduction (GO:0007265), gastrulation (GO:0007369), neuroblast proliferation (GO:0007405), negative regulation of neuroblast proliferation (GO:0007406), intracellular protein localization (GO:0008104), negative regulation of DNA replication (GO:0008156), negative regulation of cell population proliferation (GO:0008285), determination of adult lifespan (GO:0008340), mRNA transcription (GO:0009299), rRNA transcription (GO:0009303), response to salt stress (GO:0009651), response to X-ray (GO:0010165), response to gamma radiation (GO:0010332), positive regulation of gene expression (GO:0010628), cardiac muscle cell apoptotic process (GO:0010659), positive regulation of cardiac muscle cell apoptotic process (GO:0010666), glial cell proliferation (GO:0014009), viral process (GO:0016032), obsolete homolactic fermentation (GO:0019661), cerebellum development (GO:0021549), negative regulation of cell growth (GO:0030308)

GO Molecular Function (38): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), cis-regulatory region sequence-specific DNA binding (GO:0000987), core promoter sequence-specific DNA binding (GO:0001046), TFIID-class transcription factor complex binding (GO:0001094), transcription coactivator binding (GO:0001223), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), protease binding (GO:0002020), p53 binding (GO:0002039), DNA binding (GO:0003677), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), mRNA 3’-UTR binding (GO:0003730), copper ion binding (GO:0005507), zinc ion binding (GO:0008270), enzyme binding (GO:0019899), receptor tyrosine kinase binding (GO:0030971), ubiquitin protein ligase binding (GO:0031625), histone deacetylase regulator activity (GO:0035033), ATP-dependent DNA/DNA annealing activity (GO:0036310), identical protein binding (GO:0042802), histone deacetylase binding (GO:0042826), protein heterodimerization activity (GO:0046982), protein-folding chaperone binding (GO:0051087), protein phosphatase 2A binding (GO:0051721), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), 14-3-3 protein binding (GO:0071889), MDM2/MDM4 family protein binding (GO:0097371), disordered domain specific binding (GO:0097718), general transcription initiation factor binding (GO:0140296), molecular function activator activity (GO:0140677), molecular condensate scaffold activity (GO:0140693), promoter-specific chromatin binding (GO:1990841), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (21): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), replication fork (GO:0005657), transcription regulator complex (GO:0005667), nucleolus (GO:0005730), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), endoplasmic reticulum (GO:0005783), centrosome (GO:0005813), cytosol (GO:0005829), nuclear matrix (GO:0016363), PML body (GO:0016605), transcription repressor complex (GO:0017053), protein-containing complex (GO:0032991), site of double-strand break (GO:0035861), germ cell nucleus (GO:0043073), cytoskeleton (GO:0005856), membrane (GO:0016020), nuclear body (GO:0016604)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Cellular Senescence	3
TP53 Regulates Transcription of Cell Death Genes	3
Activation of BH3-only proteins	2
Transcriptional Regulation by TP53	2
Deubiquitination	2
Pre-NOTCH Expression and Processing	1
DNA Damage/Telomere Stress Induced Senescence	1
SUMO E3 ligases SUMOylate target proteins	1
Stabilization of p53	1
Chaperonin-mediated protein folding	1
Regulated Necrosis	1
DNA Double Strand Break Response	1
Signaling by Interleukins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
transcription cis-regulatory region binding	3
intracellular membrane-bounded organelle	3
nuclear lumen	3
cytoplasm	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
chordate embryonic development	2
cell fate commitment	2
DNA repair	2
regulation of DNA-templated transcription	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
protein binding	2
transition metal ion binding	2
chromosome	2
intracellular membraneless organelle	2
negative regulation of DNA-templated transcription	1
autophagy of mitochondrion	1
macroautophagy	1
anterior/posterior pattern specification	1
segmentation	1
anatomical structure formation involved in morphogenesis	1
somite development	1
apoptotic mitochondrial changes	1
apoptotic signaling pathway	1
hemopoiesis	1
cell differentiation	1
T cell activation involved in immune response	1
immune response	1
T cell proliferation	1
B cell differentiation	1
T cell differentiation	1
response to stress	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1

Protein interactions and networks

STRING

14764 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TP53	MDM2	Q00987	999
TP53	BCL2	P10415	999
TP53	BRCA1	P38398	999
TP53	EP300	Q09472	998
TP53	MDM4	O15151	998
TP53	BCL2L1	Q07817	998
TP53	MYC	P01106	997
TP53	TP53BP1	Q12888	997
TP53	CREBBP	Q92793	996
TP53	TP53BP2	Q13625	996
TP53	HSP90AA1	P07900	995
TP53	RAD51	Q06609	995
TP53	HSP90AB1	P08238	994
TP53	CCNA2	P20248	994
TP53	DNMT1	P26358	994
TP53	HDAC1	Q13547	994
TP53	HIF1A	Q16665	994

IntAct

1863 interactions, top by confidence:

A	B	Type	Score
TP53	MDM2	psi-mi:“MI:0915”(physical association)	1.000
MDM2	TP53	psi-mi:“MI:0914”(association)	1.000
MDM2	TP53	psi-mi:“MI:0915”(physical association)	1.000
MDM2	TP53	psi-mi:“MI:0407”(direct interaction)	1.000
TP53	MDM2	psi-mi:“MI:0407”(direct interaction)	1.000
TP53	TP53	psi-mi:“MI:0915”(physical association)	0.980
TP53	TP53	psi-mi:“MI:0407”(direct interaction)	0.980
TP53		psi-mi:“MI:0915”(physical association)	0.970
	TP53	psi-mi:“MI:0915”(physical association)	0.970
TP53	MDM4	psi-mi:“MI:0915”(physical association)	0.970
TP53	MDM4	psi-mi:“MI:0914”(association)	0.970
USP7	TP53	psi-mi:“MI:0407”(direct interaction)	0.970

BioGRID (6109): TP53 (Affinity Capture-Western), RCHY1 (Affinity Capture-Western), MDM2 (Affinity Capture-Western), TP53 (Reconstituted Complex), TP53 (Biochemical Activity), TP53 (Biochemical Activity), TP53 (Reconstituted Complex), TP53 (Reconstituted Complex), TSC22D3 (Affinity Capture-Western), TP53 (Affinity Capture-Western), MDM2 (Affinity Capture-Western), UBC (Affinity Capture-Western), TP53 (Affinity Capture-Western), TRIM32 (Affinity Capture-Western), HSPA1A (Affinity Capture-MS)

ESM2 similar proteins: D3ZEY4, O02019, O08674, O09185, O12946, O35954, O36006, O76808, O93379, O95248, P02340, P04637, P07193, P10360, P10361, P13481, P19838, P25035, P25799, P31266, P41685, P51664, P56423, P56424, P61260, P67938, P67939, P79734, P79892, P98150, Q00366, Q00653, Q06330, Q29537, Q3U1Y4, Q5U2N3, Q61179, Q63369, Q64662, Q6F3J0

Diamond homologs: O09185, O12946, O15350, O36006, O57538, O88898, O93379, P02340, P04637, P07193, P10360, P10361, P13481, P25035, P41685, P51664, P56423, P56424, P61260, P67938, P67939, P79734, P79820, P79892, Q00366, Q29480, Q29537, Q64662, Q8SPZ3, Q92143, Q95330, Q9H3D4, Q9JJP2, Q9JJP6, Q9TTA1, Q9TUB2, Q9W678, Q9W679, Q9WUR6, Q9XSK8

SIGNOR signaling

200 interactions.

A	Effect	B	Mechanism
MAPK3	up-regulates	TP53	phosphorylation
MAPK14	up-regulates	TP53	phosphorylation
MAPK8	“up-regulates quantity by stabilization”	TP53	phosphorylation
PLK3	“up-regulates activity”	TP53	phosphorylation
TP53	down-regulates	BIRC5	binding
TP53	“up-regulates quantity by expression”	TNFRSF10B	“transcriptional regulation”
TP53BP2	up-regulates	TP53	binding
ATR	“up-regulates quantity by stabilization”	TP53	phosphorylation
ATM	“up-regulates quantity by stabilization”	TP53	phosphorylation
MAPK8	up-regulates	TP53	phosphorylation
MAPK9	up-regulates	TP53	phosphorylation
TP53	“down-regulates quantity by repression”	BIRC5	“transcriptional regulation”
TP53	“up-regulates quantity by expression”	PMAIP1	“transcriptional regulation”
CDK2	“up-regulates activity”	TP53	phosphorylation
MAPK10	up-regulates	TP53	phosphorylation
AURKA	“up-regulates activity”	TP53	phosphorylation
TP53	up-regulates	BAX	binding
TP53	“up-regulates quantity by expression”	SIAH1	“transcriptional regulation”
NfKb-p65/p50	“up-regulates quantity by expression”	TP53
TAF1	down-regulates	TP53	phosphorylation
TP53	up-regulates	RPS6KA1
TP53	up-regulates	BAK1	binding
SMG1	up-regulates	TP53	phosphorylation
FHIT	up-regulates	TP53
TP53	“up-regulates quantity by expression”	NDRG1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 102 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SUMOylation of transcription factors	5	36.6×	3e-05
Downregulation of SMAD2/3:SMAD4 transcriptional activity	5	23.6×	3e-04
Regulation of TP53 Degradation	5	18.8×	5e-04
NOTCH1 Intracellular Domain Regulates Transcription	5	15.2×	1e-03
Regulation of TP53 Activity	8	13.6×	2e-05
Constitutive Signaling by NOTCH1 PEST Domain Mutants	5	12.6×	2e-03
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	5	12.6×	2e-03
SUMO E3 ligases SUMOylate target proteins	5	11.4×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of androgen receptor signaling pathway	5	49.3×	9e-06
positive regulation of epithelial to mesenchymal transition	5	16.7×	1e-03
rhythmic process	5	13.2×	4e-03
anatomical structure morphogenesis	6	8.8×	5e-03
DNA damage response	10	5.6×	1e-03

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate.

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 74 cancer types — ACC, ALL, AML, ANGS, ANSC, BCC, BL, BLADDER, BLCA, BRCA, CCRCC, CEAD…(+62 more).

Clinical variants and AI predictions

ClinVar

3923 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	771
Likely pathogenic	198
Uncertain significance	972
Likely benign	767
Benign	116

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012210	NM_000546.6(TP53):c.825T>A (p.Cys275Ter)	Pathogenic
1024056	NM_000546.6(TP53):c.687_695del (p.Thr230_Ile232del)	Pathogenic
1045295	NM_000546.6(TP53):c.653_655del (p.Val218_Pro219delinsAla)	Pathogenic
1050359	NM_000546.6(TP53):c.731del (p.Gly244fs)	Pathogenic
1052035	NM_000546.6(TP53):c.737_745del (p.Met246_Arg248del)	Pathogenic
1066819	NC_000017.10:g.(?7571752)(7574043_?)del	Pathogenic
1067910	NM_000546.6(TP53):c.472C>A (p.Arg158Ser)	Pathogenic
1068484	NM_000546.6(TP53):c.919+1del	Pathogenic
1068801	NM_000546.6(TP53):c.801del (p.Asn268fs)	Pathogenic
1068830	NM_000546.6(TP53):c.872_890dup (p.His297fs)	Pathogenic
1069164	NC_000017.10:g.(?7571752)(7579912_?)del	Pathogenic
1069165	NC_000017.10:g.(?7579291)(7579404_?)del	Pathogenic
1069225	NM_000546.6(TP53):c.425del (p.Pro142fs)	Pathogenic
1069253	NM_000546.6(TP53):c.268_269insGCCCCTCCTGGCCCCTGCCCCTGCCCCT (p.Ser90fs)	Pathogenic
1069265	NM_000546.6(TP53):c.403del (p.Cys135fs)	Pathogenic
1069305	NM_000546.6(TP53):c.702C>G (p.Tyr234Ter)	Pathogenic
1070469	NM_000546.6(TP53):c.205del (p.Ala69fs)	Pathogenic
1070690	NM_000546.6(TP53):c.690_702del (p.Ile232fs)	Pathogenic
1070793	NM_000546.6(TP53):c.119dup (p.Met40fs)	Pathogenic
1071474	NM_000546.6(TP53):c.662_666del (p.Glu221fs)	Pathogenic
1071800	NM_000546.6(TP53):c.245del (p.Pro82fs)	Pathogenic
1071812	NM_000546.6(TP53):c.665dup (p.Pro223fs)	Pathogenic
1072958	NM_000546.6(TP53):c.1014dup (p.Glu339fs)	Pathogenic
1073381	NM_000546.6(TP53):c.321C>G (p.Tyr107Ter)	Pathogenic
1073670	NM_000546.6(TP53):c.458_462dup (p.Thr155fs)	Pathogenic
1074338	NM_000546.6(TP53):c.723del (p.Cys242fs)	Pathogenic
1075116	NM_000546.6(TP53):c.93del (p.Leu32fs)	Pathogenic
1075217	NC_000017.10:g.(?7577489)(7577647_?)del	Pathogenic
1075218	NC_000017.10:g.(?7577009)(7579922_?)del	Pathogenic
1075219	NC_000017.10:g.(?7571752)(7606804_?)del	Pathogenic

SpliceAI

1638 predictions. Top by Δscore:

Variant	Effect	Δscore
17:7670604:CTCA:C	donor_loss	1.0000
17:7670605:TCA:T	donor_loss	1.0000
17:7670606:CA:C	donor_loss	1.0000
17:7670607:A:T	donor_loss	1.0000
17:7670608:C:A	donor_loss	1.0000
17:7670711:CGGAT:C	acceptor_gain	1.0000
17:7670712:GGAT:G	acceptor_gain	1.0000
17:7670713:GAT:G	acceptor_gain	1.0000
17:7670714:AT:A	acceptor_gain	1.0000
17:7670716:C:CC	acceptor_gain	1.0000
17:7670716:CTGC:C	acceptor_loss	1.0000
17:7670720:A:T	acceptor_gain	1.0000
17:7670723:A:T	acceptor_gain	1.0000
17:7670725:C:CT	acceptor_gain	1.0000
17:7670726:A:T	acceptor_gain	1.0000
17:7673529:TAGTA:T	donor_loss	1.0000
17:7673530:AGTAC:A	donor_gain	1.0000
17:7673531:GTACC:G	donor_loss	1.0000
17:7673532:TA:T	donor_loss	1.0000
17:7673534:C:A	donor_loss	1.0000
17:7673604:CAGTG:C	acceptor_gain	1.0000
17:7673605:AGTG:A	acceptor_gain	1.0000
17:7673606:GTG:G	acceptor_gain	1.0000
17:7673607:TG:T	acceptor_gain	1.0000
17:7673607:TGC:T	acceptor_loss	1.0000
17:7673608:GCTA:G	acceptor_loss	1.0000
17:7673609:C:CC	acceptor_gain	1.0000
17:7673609:CTAG:C	acceptor_loss	1.0000
17:7673696:CTTA:C	donor_loss	1.0000
17:7673697:TTA:T	donor_loss	1.0000

AlphaMissense

2569 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:7673778:T:A	D281V	1.000
17:7673778:T:C	D281G	1.000
17:7673778:T:G	D281A	1.000
17:7673780:T:A	R280S	1.000
17:7673780:T:G	R280S	1.000
17:7673781:C:A	R280I	1.000
17:7673781:C:G	R280T	1.000
17:7673791:A:G	C277R	1.000
17:7673796:C:T	C275Y	1.000
17:7673797:A:G	C275R	1.000
17:7674216:C:A	R249S	1.000
17:7674216:C:G	R249S	1.000
17:7674238:C:T	C242Y	1.000
17:7674243:A:C	S240R	1.000
17:7674243:A:T	S240R	1.000
17:7674245:T:G	S240R	1.000
17:7674249:A:C	C238W	1.000
17:7674250:C:A	C238F	1.000
17:7674250:C:G	C238S	1.000
17:7674250:C:T	C238Y	1.000
17:7674251:A:G	C238R	1.000
17:7674251:A:T	C238S	1.000
17:7675085:C:G	C176S	1.000
17:7675086:A:G	C176R	1.000
17:7675086:A:T	C176S	1.000
17:7675210:A:C	F134L	1.000
17:7675210:A:T	F134L	1.000
17:7675212:A:G	F134L	1.000
17:7673775:C:G	R282P	0.999
17:7673777:G:C	D281E	0.999

dbSNP variants (sampled 300 via entrez): RS1000042393 (17:7677294 G>C), RS1000105827 (17:7667960 C>G,T), RS1000197233 (17:7680021 G>A), RS1000256867 (17:7673550 T>A,C,G), RS1000314275 (17:7686758 G>A), RS1000319509 (17:7672889 T>A,C), RS1000589618 (17:7672369 G>A), RS1000619666 (17:7679585 T>A), RS1000646183 (17:7679074 C>A,T), RS1000714446 (17:7680286 A>T), RS1000743410 (17:7685736 C>G), RS1000879642 (17:7683876 T>A,C), RS1001269361 (17:7671675 G>C), RS1001321246 (17:7682482 T>C), RS1001489509 (17:7677852 A>G)

Disease associations

OMIM: gene MIM:191170 | disease phenotypes: MIM:151623, MIM:609266, MIM:259500, MIM:114500, MIM:114550, MIM:202300, MIM:260500, MIM:614740, MIM:260350, MIM:114480, MIM:137800, MIM:618165, MIM:601518, MIM:188550, MIM:236000, MIM:151400, MIM:613659, MIM:601626, MIM:603956, MIM:275355, MIM:109800, MIM:254500, MIM:133239, MIM:167000, MIM:127550, MIM:613399, MIM:612555, MIM:604370, MIM:613988, MIM:105650

GenCC curated gene-disease

Disease	Classification	Inheritance
breast cancer	Definitive	Autosomal dominant
Li-Fraumeni syndrome 1	Definitive	Autosomal dominant
Li-Fraumeni syndrome	Definitive	Autosomal dominant
adrenocortical carcinoma, hereditary	Strong	Autosomal dominant
sarcoma	Strong	Autosomal dominant
colorectal cancer	Moderate	Autosomal dominant
bone marrow failure syndrome 5	Moderate	Autosomal dominant
choroid plexus carcinoma	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Li-Fraumeni syndrome	Definitive	AD

Mondo (76): hereditary neoplastic syndrome (MONDO:0015356), Li-Fraumeni syndrome (MONDO:0018875), bone osteosarcoma (MONDO:0002629), colorectal cancer (MONDO:0005575), hepatocellular carcinoma (MONDO:0007256), adrenocortical carcinoma, hereditary (MONDO:0008734), choroid plexus papilloma (MONDO:0009837), basal cell carcinoma, susceptibility to, 7 (MONDO:0013876), familial pancreatic carcinoma (MONDO:0015278), nasopharyngeal carcinoma (MONDO:0015459), hereditary breast carcinoma (MONDO:0016419), glioma susceptibility 1 (MONDO:0024498), bone marrow failure syndrome 5 (MONDO:0032573), ovarian neoplasm (MONDO:0021068), prostate cancer, hereditary, 1 (MONDO:0011098)

Orphanet (39): Inherited cancer-predisposing syndrome (Orphanet:140162), Li-Fraumeni syndrome (Orphanet:524), Familial pancreatic carcinoma (Orphanet:1333), Nasopharyngeal carcinoma (Orphanet:150), Adrenocortical carcinoma (Orphanet:1501), Hereditary breast cancer (Orphanet:227535), Choroid plexus carcinoma (Orphanet:251899), Papilloma of choroid plexus (Orphanet:2807), Osteosarcoma (Orphanet:668), Hepatocellular carcinoma (Orphanet:88673), Familial prostate cancer (Orphanet:1331), Classic Hodgkin lymphoma (Orphanet:391), B-cell chronic lymphocytic leukemia (Orphanet:67038), Diffuse large B-cell lymphoma (Orphanet:544), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

224 total (30 of 224 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000029	Testicular atrophy
HP:0000080	Abnormality of reproductive system physiology
HP:0000135	Hypogonadism
HP:0000141	Amenorrhea
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000505	Visual impairment
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000725	Psychotic episodes
HP:0000726	Dementia
HP:0000737	Irritability
HP:0000739	Anxiety
HP:0000819	Diabetes mellitus
HP:0000822	Hypertension
HP:0000859	Increased circulating aldosterone concentration
HP:0000869	Secondary amenorrhea
HP:0000876	Oligomenorrhea
HP:0000939	Osteoporosis
HP:0000944	Abnormal metaphysis morphology
HP:0000952	Jaundice
HP:0000953	Hyperpigmentation of the skin
HP:0000963	Thin skin
HP:0000975	Hyperhidrosis
HP:0000978	Bruising susceptibility
HP:0000979	Purpura
HP:0000998	Hypertrichosis

GWAS associations

50 associations (top):

Study	Trait	p-value
GCST001250_1	Basal cell carcinoma	2.000000e-20
GCST002331_9	Basal cell carcinoma	4.000000e-22
GCST002568_2	Esophageal squamous cell carcinoma	3.000000e-13
GCST002842_7	Basal cell carcinoma	1.000000e-20
GCST002925_8	Sex hormone levels	1.000000e-15
GCST003726_18	Basal cell carcinoma	2.000000e-10
GCST004278_28	Pulse pressure	2.000000e-10
GCST004278_46	Pulse pressure	2.000000e-07
GCST004280_69	Diastolic blood pressure	1.000000e-13
GCST004347_18	Glioma	9.000000e-38
GCST004348_11	Non-glioblastoma glioma	5.000000e-27
GCST004349_11	Glioblastoma	5.000000e-29
GCST004510_7	Sporadic neuroblastoma	1.000000e-08
GCST004630_210	Mean corpuscular hemoglobin	6.000000e-09
GCST005931_14	Glioma	3.000000e-17
GCST005931_15	Glioma	2.000000e-12
GCST005932_8	Glioblastoma	1.000000e-14
GCST005932_9	Glioblastoma	2.000000e-09
GCST005933_4	Non-glioblastoma glioma	1.000000e-10
GCST005933_5	Non-glioblastoma glioma	4.000000e-08
GCST006462_43	Uterine fibroids	4.000000e-37
GCST006480_12	Glioblastoma (age-stratified)	9.000000e-16
GCST006480_19	Glioblastoma (age-stratified)	3.000000e-08
GCST006480_6	Glioblastoma (age-stratified)	4.000000e-13
GCST007094_117	Diastolic blood pressure	1.000000e-08
GCST007096_51	Pulse pressure	4.000000e-13
GCST007268_61	Diastolic blood pressure	3.000000e-15
GCST007269_302	Pulse pressure	8.000000e-23
GCST008362_19	Birth weight	2.000000e-11
GCST008423_10	Uterine fibroids	3.000000e-33

EFO canonical traits (16, from GWAS)

EFO ID	Trait name
EFO:0004696	sex hormone-binding globulin measurement
EFO:0004730	hormone measurement
EFO:0005763	pulse pressure measurement
EFO:0006336	diastolic blood pressure
EFO:0004527	mean corpuscular hemoglobin
EFO:0004847	age at onset
EFO:0004344	birth weight
EFO:0010176	keratinocyte carcinoma
EFO:0007783	mosaic loss of chromosome Y measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004632	nevus count
EFO:0004346	neuroimaging measurement
EFO:0004980	appendicular lean mass
EFO:0007989	monocyte percentage of leukocytes
EFO:0010701	mean reticulocyte volume
EFO:0004305	erythrocyte count

MeSH disease descriptors (32)

Descriptor	Name	Tree numbers
D000230	Adenocarcinoma	C04.557.470.200.025
D029503	Anemia, Diamond-Blackfan	C15.378.050.085.080.090; C15.378.050.750.500; C15.378.190.223.500.500.090; C16.320.077.090
D001254	Astrocytoma	C04.557.465.625.600.380.080; C04.557.470.670.380.080; C04.557.580.625.600.380.080
D001943	Breast Neoplasms	C04.588.180; C17.800.090.500
D006528	Carcinoma, Hepatocellular	C04.557.470.200.025.255; C04.588.274.623.160; C06.301.623.160; C06.552.697.160
D002285	Carcinoma, Intraductal, Noninfiltrating	C04.557.470.200.025.275; C04.557.470.200.240.187.250; C04.557.470.615.275
D002294	Carcinoma, Squamous Cell	C04.557.470.200.400; C04.557.470.700.400
D003110	Colonic Neoplasms	C04.588.274.476.411.307.180; C06.301.371.411.307.180; C06.405.249.411.307.180; C06.405.469.158.356.180; C06.405.469.491.307.180
D019871	Dyskeratosis Congenita	C15.378.190.223.500.750; C16.131.831.150; C16.320.322.108; C16.320.850.235; C17.800.804.150; C17.800.827.235
D018197	Hepatoblastoma	C04.557.435.380
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D015451	Leukemia, Lymphocytic, Chronic, B-Cell	C04.557.337.428.080.125; C15.378.508.428.080.125; C15.604.515.560.080.125; C20.683.515.528.080.125; C23.550.291.500.483
D007947	Leukemia, Megakaryoblastic, Acute	C04.557.337.539.275.450; C15.378.508.539.275.450
D015470	Leukemia, Myeloid, Acute	C04.557.337.539.275; C15.378.508.539.275
D016864	Li-Fraumeni Syndrome	C04.700.600; C16.320.700.600; C18.452.284.520
D008223	Lymphoma	C04.557.386; C15.604.515.569; C20.683.515.761
D016403	Lymphoma, Large B-Cell, Diffuse	C04.557.386.480.150.585; C15.604.515.569.480.150.585; C20.683.515.761.480.150.585
D008228	Lymphoma, Non-Hodgkin	C04.557.386.480; C15.604.515.569.480; C20.683.515.761.480
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650
D000077274	Nasopharyngeal Carcinoma	C04.557.470.200.623; C04.588.443.665.710.650.500; C07.550.350.650.500; C07.550.745.650.500; C09.647.710.650.500; C09.775.350.650.500; C09.775.549.650.500
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
D020288	Papilloma, Choroid Plexus	C04.588.614.250.195.205.200.500; C10.228.140.211.280.300.500; C10.551.240.250.200.200.500
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
D012208	Rhabdomyosarcoma	C04.557.450.590.550.660; C04.557.450.795.550.660
D012509	Sarcoma	C04.557.450.795
D013274	Stomach Neoplasms	C04.588.274.476.767; C06.301.371.767; C06.405.249.767; C06.405.748.789
D065646	Thyroid Carcinoma, Anaplastic	C04.557.470.200.725
C565972	Adrenocortical Carcinoma, Hereditary (supp.)
C562840	Breast Cancer, Familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (11): CHEMBL1907611 (PROTEIN-PROTEIN INTERACTION), CHEMBL2221344 (PROTEIN-PROTEIN INTERACTION), CHEMBL3301383 (PROTEIN-PROTEIN INTERACTION), CHEMBL3883306 (PROTEIN-PROTEIN INTERACTION), CHEMBL3885543 (PROTEIN-PROTEIN INTERACTION), CHEMBL3885544 (PROTEIN-PROTEIN INTERACTION), CHEMBL3885545 (PROTEIN-PROTEIN INTERACTION), CHEMBL4096 (SINGLE PROTEIN), CHEMBL4879538 (PROTEIN-PROTEIN INTERACTION), CHEMBL6066147 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

196 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,556,691 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL572	NITROFURANTOIN	4	26,231
CHEMBL231884	DIOSMIN	4	4,880
CHEMBL5314346	VERTEPORFIN	4
CHEMBL1014	CANDESARTAN CILEXETIL	4	11,194
CHEMBL1018	DIENESTROL	4	5,607
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL107	COLCHICINE	4	93,932
CHEMBL1070	NABUMETONE	4	55,063
CHEMBL1082607	SALMETEROL XINAFOATE	4	15,201
CHEMBL1083993	AMIODARONE HYDROCHLORIDE	4	3,265
CHEMBL1103	FURAZOLIDONE	4	14,492
CHEMBL1113	AMOXAPINE	4	20,128
CHEMBL1116	RALOXIFENE HYDROCHLORIDE	4	28,574
CHEMBL1200326	NICARDIPINE HYDROCHLORIDE	4	3,903
CHEMBL1200348	SULCONAZOLE NITRATE	4	3,129
CHEMBL1200471	PYRITHIONE ZINC	4	24,834
CHEMBL1200559	LACTIC ACID	4	1,162,486
CHEMBL1200585	OXYMETHOLONE	4	5,113
CHEMBL1200596	CHLOROXINE	4	1,792
CHEMBL1200627	PROPIOLACTONE	4	20,542
CHEMBL1200710	CLOMIPRAMINE HYDROCHLORIDE	4
CHEMBL1200868	PHENYL AMINOSALICYLATE	4
CHEMBL1200916	THIORIDAZINE HYDROCHLORIDE	4
CHEMBL1200964	AMITRIPTYLINE HYDROCHLORIDE	4
CHEMBL1200970	ETHOPROPAZINE HYDROCHLORIDE	4
CHEMBL1201001	MECHLORETHAMINE HYDROCHLORIDE	4
CHEMBL1201049	ECONAZOLE NITRATE	4
CHEMBL1201102	TRIFLUPROMAZINE HYDROCHLORIDE	4
CHEMBL1201154	PROCHLORPERAZINE EDISYLATE	4
CHEMBL121663	DEQUALINIUM CHLORIDE	4

Clinical evidence (CIViC)

Drug × variant × indication: 73 predictive associations from 74 curated evidence items; also 138 functional, 48 prognostic, 8 oncogenic, 4 predisposing, 1 diagnostic.

Variant	Therapy	Indication	Effect	Level	CIViC
TP53 Deleterious Mutation	Adjuvant Chemotherapy	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID1148
TP53 Deleterious Mutation	Pazopanib	Sarcoma	Sensitivity/Response	CIViC B	EID1170
TP53 Mutation	VEGF/VEGFR Inhibitors	Cancer	Sensitivity/Response	CIViC B	EID11709
TP53 Mutation	Azacitidine + Eprenetapopt	Myelodysplastic Syndrome	Sensitivity/Response	CIViC B	EID12029
TP53 Mutation	Eprenetapopt + Pembrolizumab	Cancer	Sensitivity/Response	CIViC B	EID12033
TP53 Mutation	Alemtuzumab	Chronic Lymphocytic Leukemia	Sensitivity/Response	CIViC B	EID1481
TP53 Mutation	Gemcitabine	Pancreatic Cancer	Sensitivity/Response	CIViC B	EID8282
TP53 Mutation	Chemotherapy	Gastric Adenocarcinoma	Sensitivity/Response	CIViC B	EID850
TP53 Overexpression	Cisplatin + Mitomycin + Etoposide	Stomach Cancer	Sensitivity/Response	CIViC B	EID2799
TP53 R249	Doxorubicin	Breast Cancer	Sensitivity/Response	CIViC B	EID399
TP53 Wildtype	Adjuvant Chemotherapy	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID1149
TP53 Wildtype	RG7112	Leukemia	Sensitivity/Response	CIViC B	EID2965
TP53 Wildtype	Capecitabine + Oxaliplatin + Cetuximab	Colorectal Cancer	Sensitivity/Response	CIViC B	EID875
TP53 Wildtype	Chemotherapy	Esophageal Carcinoma	Sensitivity/Response	CIViC B	EID906
TP53 ALTERATION	Carboplatin + Cisplatin	Ovarian Cancer	Resistance	CIViC B	EID2771
TP53 DNA Binding Domain Mutation	Tamoxifen	Breast Cancer	Resistance	CIViC B	EID2783
TP53 Deleterious Mutation	RG7112	Leukemia	Resistance	CIViC B	EID2966
TP53 Mutation	Venetoclax	Chronic Lymphocytic Leukemia/small Lymphocytic Lymphoma	Resistance	CIViC B	EID6074
TP53 Mutation	Temozolomide	Glioblastoma	Resistance	CIViC B	EID7978
TP53 Overexpression	Carboplatin + Cisplatin	Ovarian Cancer	Resistance	CIViC B	EID3013
TP53 Y220C	Rezatapopt	Cancer	Sensitivity/Response	CIViC C	EID12297 +1
TP53 Mutation	Cisplatin + Etoposide + Doxorubicin	Stomach Carcinoma	Sensitivity/Response	CIViC C	EID2820
TP53 Mutation	Vismodegib	Medulloblastoma SHH Activated And TP53 Mutant	Sensitivity/Response	CIViC C	EID8348
TP53 R175H	EAP Protocol	Stomach Carcinoma	Sensitivity/Response	CIViC C	EID2310
TP53 R175H OR TP53 H193R	Pazopanib + Vorinostat	Sarcoma	Sensitivity/Response	CIViC C	EID7540
TP53 R213P	EAP Protocol	Stomach Carcinoma	Sensitivity/Response	CIViC C	EID2819
TP53 R273C	Etoposide + Mitomycin + Cisplatin	Stomach Carcinoma	Sensitivity/Response	CIViC C	EID2292
TP53 R273C OR TP53 G245S OR TP53 R213*	Pazopanib + Vorinostat	Colorectal Cancer	Sensitivity/Response	CIViC C	EID12732
TP53 R282L	EAP Protocol	Stomach Carcinoma	Sensitivity/Response	CIViC C	EID2818
TP53 Y220C	Mitomycin + Cisplatin + Etoposide	Stomach Carcinoma	Sensitivity/Response	CIViC C	EID2306

+43 more predictive associations (showing top 30 by evidence level).

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1042522	Toxicity	3	antineoplastic agents	Drug Toxicity
rs1042522	Efficacy	3	Platinum compounds	Overall survival
rs4968187	Toxicity	3	cyclophosphamide;epirubicin;fluorouracil	Breast Neoplasms;Neutropenia

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1042522	TP53, WRAP53	3	5.00	2	antineoplastic agents;Platinum compounds
rs4968187	TP53	3	0.00	1	cyclophosphamide;epirubicin;fluorouracil

Binding affinities (BindingDB)

719 measured of 725 human assays (725 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-[3-[(6S)-5-(5-chloro-2-methylphenyl)-6-(4-chlorophenyl)-4-oxo-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxyphenyl]acetic acid	IC50	0.061 nM	US-9365576: Pyrrolopyrrolidinone compounds
(6S)-5-(5-chloro-2-methylphenyl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-4-one	IC50	0.065 nM	US-9365576: Pyrrolopyrrolidinone compounds
5-(5-chloro-2-methylphenyl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-4-one	IC50	0.068 nM	US-9365576: Pyrrolopyrrolidinone compounds
4-[(6S)-5-(5-chloro-1-methyl-6-oxo-3-pyridinyl)-2-[2-(dimethylamino)-4-methoxypyrimidin-5-yl]-4-oxo-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-6-yl]benzonitrile	IC50	0.069 nM	US-9365576: Pyrrolopyrrolidinone compounds
(6S)-6-(4-chloro-3-fluorophenyl)-5-(5-chloro-2-oxopiperidin-3-yl)-2-[2-(dimethylamino)-4-methoxypyrimidin-5-yl]-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-4-one	IC50	0.071 nM	US-9365576: Pyrrolopyrrolidinone compounds
3-[(6S)-5-(5-chloro-2-methylphenyl)-6-(4-chlorophenyl)-4-oxo-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxy-N,N-dimethylbenzamide	IC50	0.075 nM	US-9365576: Pyrrolopyrrolidinone compounds
(6S)-2-(2-amino-4-methoxypyrimidin-5-yl)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-[(2R)-1-methoxypropan-2-yl]-6H-pyrrolo[3,4-b]pyrrol-4-one	IC50	0.078 nM	US-9365576: Pyrrolopyrrolidinone compounds
(6S)-5-(3-chloro-2-oxo-3H-pyridin-5-yl)-6-(4-chlorophenyl)-2-[2-(dimethylamino)-4-methoxypyrimidin-5-yl]-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-4-one	IC50	0.079 nM	US-9365576: Pyrrolopyrrolidinone compounds
3-[(6S)-5-(5-chloro-2-methylphenyl)-6-(4-chlorophenyl)-4-oxo-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxybenzoic acid	IC50	0.08 nM	US-9365576: Pyrrolopyrrolidinone compounds
(6S)-5-(5-chloro-1-methyl-6-oxo-3-pyridinyl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-4-one	IC50	0.087 nM	US-9365576: Pyrrolopyrrolidinone compounds
3-[(6S)-6-(4-chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-4-oxo-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxy-N-methylbenzamide	IC50	0.094 nM	US-9365576: Pyrrolopyrrolidinone compounds
3-[(6S)-5-(5-chloro-2-methylphenyl)-6-(4-chlorophenyl)-4-oxo-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxy-N-methylbenzamide	IC50	0.095 nM	US-9365576: Pyrrolopyrrolidinone compounds
2-[(3R,5R,6S)-1-[(1S)-2-tert-butylsulfonyl-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.0962 nM	US-8952036: Benzoic acid derivative MDM2 inhibitor for the treatment of cancer
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-[difluoromethyl(ethylsulfonyl)amino]ethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9593129: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-[cyclopropylsulfonyl(difluoromethyl)amino]ethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9593129: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-(N-ethylsulfonyl-2-fluoroanilino)ethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9296736: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-[(2S)-1-[(3-methyloxetan-3-yl)methylsulfonyl]butan-2-yl]-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9593129: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-1-[(2S)-1-[(2R)-butan-2-yl]sulfonylbutan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9593129: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-[(3-methyloxetan-3-yl)methylsulfonyl]ethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9593129: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-(cyclopropylmethylsulfonyl)ethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9593129: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-2-cyclohexylsulfonyl-1-cyclopropylethyl]-3-ethyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9593129: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-1-[(2S)-1-tert-butylsulfonylbutan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9593129: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-ethylsulfonylethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9593129: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-cyclopropylsulfonylethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9593129: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-propan-2-ylsulfonylethyl]-3-ethyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9593129: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-pentan-3-ylsulfonylethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9593129: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2S,3S)-2-ethylsulfonylpentan-3-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9593129: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R)-1-[(1S)-2-(tert-butylsulfamoyl)-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9593129: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-1-[(2S)-1-tert-butylsulfonylbutan-2-yl]-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9593129: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-[(2S)-1-propan-2-ylsulfonylbutan-2-yl]piperidin-3-yl]acetic acid	IC50	0.1 nM	US-9593129: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-(propan-2-ylsulfamoyl)ethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9296736: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-morpholin-4-ylsulfonylethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9296736: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-1-[(2S)-1-tert-butylsulfonylbutan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9296736: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-pyrrolidin-1-ylsulfonylethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9593129: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-methylsulfonylethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9593129: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-propan-2-ylsulfonylethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	IC50	0.1 nM	US-9593129: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
3-[5-(5-chloro-2-methylphenyl)-6-(4-chlorophenyl)-4-oxo-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxybenzamide	IC50	0.104 nM	US-9365576: Pyrrolopyrrolidinone compounds
5-(5-chloro-2-methylphenyl)-6-(4-chlorophenyl)-2-[2-methoxy-5-(morpholine-4-carbonyl)phenyl]-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-4-one	IC50	0.106 nM	US-9365576: Pyrrolopyrrolidinone compounds
5-(5-chloro-2-oxopiperidin-3-yl)-6-(4-chlorophenyl)-2-[2-(dimethylamino)-4-methoxypyrimidin-5-yl]-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-4-one	IC50	0.106 nM	US-9365576: Pyrrolopyrrolidinone compounds
4-[(6S)-5-(5-chloro-1-methyl-6-oxo-3-pyridinyl)-2-(2,4-dimethoxypyrimidin-5-yl)-4-oxo-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-6-yl]-2-fluorobenzonitrile	IC50	0.107 nM	US-9365576: Pyrrolopyrrolidinone compounds
4-[(6S)-5-(5-chloro-1-methyl-6-oxo-3-pyridinyl)-2-(2,4-dimethoxypyrimidin-5-yl)-4-oxo-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-6-yl]benzonitrile	IC50	0.108 nM	US-9365576: Pyrrolopyrrolidinone compounds
5-(5-chloro-2-methylphenyl)-6-(4-chlorophenyl)-2-(5-methoxy-1-methyl-2-oxo-4-pyridinyl)-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-4-one	IC50	0.11 nM	US-9365576: Pyrrolopyrrolidinone compounds
5-(5-chloro-2-methylphenyl)-6-(4-chlorophenyl)-2-[5-(hydroxymethyl)-2-methoxyphenyl]-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-4-one	IC50	0.113 nM	US-9365576: Pyrrolopyrrolidinone compounds
3-[5-(5-chloro-2-methylphenyl)-6-(4-chlorophenyl)-4-oxo-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxy-N-(2-methylsulfonylethyl)benzamide	IC50	0.115 nM	US-9365576: Pyrrolopyrrolidinone compounds
2-[3-[5-(5-chloro-2-methylphenyl)-6-(4-chlorophenyl)-4-oxo-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxyphenyl]acetamide	IC50	0.115 nM	US-9365576: Pyrrolopyrrolidinone compounds
3-[5-(5-chloro-2-methylphenyl)-6-(4-chlorophenyl)-4-oxo-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxy-N-methylbenzamide	IC50	0.116 nM	US-9365576: Pyrrolopyrrolidinone compounds
3-[(6S)-5-(3-chloro-2-fluorophenyl)-6-(4-chloro-2-methylphenyl)-4-oxo-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxy-N-methylbenzamide	IC50	0.119 nM	US-9365576: Pyrrolopyrrolidinone compounds
6-(4-chloro-3-fluorophenyl)-5-(5-chloro-2-oxopiperidin-3-yl)-2-[2-(dimethylamino)-4-methoxypyrimidin-5-yl]-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-4-one	IC50	0.119 nM	US-9365576: Pyrrolopyrrolidinone compounds
5-(5-chloro-1-methyl-6-oxo-3-pyridinyl)-6-(4-chlorophenyl)-2-[2-(dimethylamino)-4-methoxypyrimidin-5-yl]-4-oxo-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrole-3-carbonitrile	IC50	0.121 nM	US-9365576: Pyrrolopyrrolidinone compounds
5-(5-chloro-2-fluoro-1-methyl-6-oxo-3-pyridinyl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-propan-2-yl-6H-pyrrolo[3,4-b]pyrrol-4-one	IC50	0.122 nM	US-9365576: Pyrrolopyrrolidinone compounds

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.89	IC50	0.013	nM	CHEMBL5283210
10.72	IC50	0.019	nM	CHEMBL5272028
10.21	IC50	0.061	nM	CHEMBL3892862
10.19	IC50	0.065	nM	CHEMBL3901716
10.17	IC50	0.068	nM	CHEMBL3945756
10.16	IC50	0.069	nM	CHEMBL3911501
10.15	IC50	0.071	nM	CHEMBL3920430
10.12	IC50	0.075	nM	CHEMBL3916525
10.11	IC50	0.078	nM	CHEMBL4110580
10.10	IC50	0.08	nM	CHEMBL3893972
10.10	IC50	0.079	nM	CHEMBL3928320
10.06	IC50	0.087	nM	CHEMBL3895404
10.03	IC50	0.094	nM	CHEMBL3937629
10.02	IC50	0.095	nM	CHEMBL3916664
10.00	IC50	0.1	nM	CHEMBL3965232
10.00	IC50	0.1	nM	CHEMBL3963590
10.00	IC50	0.1	nM	CHEMBL4112633
10.00	IC50	0.1	nM	CHEMBL3915847
10.00	IC50	0.1	nM	CHEMBL3983607
10.00	IC50	0.1	nM	CHEMBL3986408
10.00	IC50	0.1	nM	CHEMBL3899040
10.00	IC50	0.1	nM	CHEMBL3929623
10.00	IC50	0.1	nM	CHEMBL3125527
10.00	IC50	0.1	nM	CHEMBL3952401
10.00	IC50	0.1	nM	CHEMBL4106749
10.00	IC50	0.1	nM	CHEMBL3125697
10.00	IC50	0.1	nM	CHEMBL3125537
10.00	IC50	0.1	nM	CHEMBL3894720
10.00	IC50	0.1	nM	CHEMBL3125701
10.00	IC50	0.1	nM	CHEMBL3956221
10.00	IC50	0.1	nM	CHEMBL4112965
10.00	IC50	0.1	nM	CHEMBL3958045
10.00	IC50	0.1	nM	CHEMBL4114145
10.00	IC50	0.1	nM	CHEMBL3318760
10.00	IC50	0.1	nM	CHEMBL3318767
10.00	IC50	0.1	nM	CHEMBL3125521
10.00	IC50	0.1	nM	CHEMBL3904145
10.00	IC50	0.1	nM	CHEMBL3909721
10.00	IC50	0.1	nM	CHEMBL5272028
9.98	IC50	0.104	nM	CHEMBL3935668
9.97	IC50	0.106	nM	CHEMBL3908421
9.97	IC50	0.106	nM	CHEMBL3975933
9.97	IC50	0.108	nM	CHEMBL3914063
9.97	IC50	0.106	nM	CHEMBL3895404
9.97	IC50	0.107	nM	CHEMBL3894082
9.96	IC50	0.11	nM	CHEMBL3940794
9.95	IC50	0.113	nM	CHEMBL3926314
9.94	IC50	0.116	nM	CHEMBL3925236
9.94	IC50	0.115	nM	CHEMBL3902132
9.94	IC50	0.115	nM	CHEMBL3889539

PubChem BioAssay actives

854 with measured affinity, of 3203 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(3R,4S,5S,6R)-2-[4-(2,4-difluorophenyl)triazol-1-yl]-6-(hydroxymethyl)oxane-3,4,5-triol	1928056: Inhibition of human DM2-p53 protein-protein interaction by fluorescence anisotropy analysis	ic50	<0.0001	uM
(3R,4S,5S,6R)-2-[4-[(1S)-1-(3-fluorophenyl)-1-hydroxyethyl]triazol-1-yl]-6-(hydroxymethyl)oxane-3,4,5-triol	1928056: Inhibition of human DM2-p53 protein-protein interaction by fluorescence anisotropy analysis	ic50	<0.0001	uM
(4S)-5-[3-chloro-5-[2-(dimethylamino)ethoxy]phenyl]-4-(4-chloro-2-methylphenyl)-2-(2-methoxyphenyl)-3-propan-2-yl-4H-pyrrolo[3,4-c]pyrazol-6-one	1873011: Inhibition of recombinant human MDM2/p53 interaction	ic50	0.0001	uM
3-[[6-chloro-3-[3-[(1S)-1-(2,4-dichlorophenyl)ethyl]-5-phenylimidazol-4-yl]-1H-indole-2-carbonyl]amino]-4-[4-(2-oxo-1,3-oxazinan-3-yl)piperidin-1-yl]benzoic acid	2024720: Inhibition of MDM2/p53 (unknown origin) interaction by TR-FRET assay	ic50	0.0001	uM
6-[[(1R)-1-cyclobutylethyl]amino]-7-[(4-methylcyclohexyl)methyl]-8-[(3R)-3-phenylmorpholin-4-yl]purine-2-carboxylic acid	1807775: Inhibition of N-terminal thioredoxin-His6 tagged HDM2 (17 to 125 residues)/p53 protein-protein interaction (unknown origin) incubated for 2 hrs by TR-FRET assay	ic50	0.0002	uM
3-[4-(5-chloro-3-pyridinyl)-2-[(R)-cyclopropyl(ethoxy)methyl]-3-[(1R)-1-(4-methylcyclohexyl)ethyl]imidazo[4,5-c]pyridin-6-yl]-4H-1,2,4-oxadiazol-5-one	1807775: Inhibition of N-terminal thioredoxin-His6 tagged HDM2 (17 to 125 residues)/p53 protein-protein interaction (unknown origin) incubated for 2 hrs by TR-FRET assay	ic50	0.0003	uM
4-[(3S,5’S,7’R,7’aR)-6-chloro-7’-(3-chlorophenyl)-5’-(2,2-dimethylpropyl)-1’-oxospiro[1,2-dihydroindole-3,6’-3,5,7,7a-tetrahydropyrrolo[1,2-c]imidazole]-2’-yl]-3-methoxybenzoic acid	2075718: Inhibition of MDM2/p53 (unknown origin) interaction by fluorescence polarization assay	ki	0.0004	uM
3-[6-(5-chloro-3-pyridinyl)-7-[(4-methylcyclohexyl)methyl]-8-[(3R)-3-phenylmorpholin-4-yl]purin-2-yl]-4H-1,2,4-oxadiazol-5-one	1807775: Inhibition of N-terminal thioredoxin-His6 tagged HDM2 (17 to 125 residues)/p53 protein-protein interaction (unknown origin) incubated for 2 hrs by TR-FRET assay	ic50	0.0005	uM
3-[2-[(4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-cyclopenta[b][1,4]oxazin-4-yl]-4-(5-chloro-3-pyridinyl)-3-[(4-methylcyclohexyl)methyl]imidazo[4,5-c]pyridin-6-yl]-4H-1,2,4-oxadiazol-5-one	1807775: Inhibition of N-terminal thioredoxin-His6 tagged HDM2 (17 to 125 residues)/p53 protein-protein interaction (unknown origin) incubated for 2 hrs by TR-FRET assay	ic50	0.0006	uM
3-[4-(5-chloro-3-pyridinyl)-3-[(4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]imidazo[4,5-c]pyridin-6-yl]-4H-1,2,4-oxadiazol-5-one	1807775: Inhibition of N-terminal thioredoxin-His6 tagged HDM2 (17 to 125 residues)/p53 protein-protein interaction (unknown origin) incubated for 2 hrs by TR-FRET assay	ic50	0.0006	uM
3-[6-[[(1R)-1-cyclobutylethyl]amino]-7-[(4-methylcyclohexyl)methyl]-8-[(3R)-3-phenylmorpholin-4-yl]purin-2-yl]-4H-1,2,4-oxadiazol-5-one	1807775: Inhibition of N-terminal thioredoxin-His6 tagged HDM2 (17 to 125 residues)/p53 protein-protein interaction (unknown origin) incubated for 2 hrs by TR-FRET assay	ic50	0.0006	uM
4-[(3S,5’S,7’R,7’aR)-6-chloro-7’-(3-chlorophenyl)-5’-[(1-methylcyclopentyl)methyl]-1’-oxospiro[1,2-dihydroindole-3,6’-3,5,7,7a-tetrahydropyrrolo[1,2-c]imidazole]-2’-yl]-3-methoxybenzoic acid	2075718: Inhibition of MDM2/p53 (unknown origin) interaction by fluorescence polarization assay	ki	0.0006	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-[(2S)-3-methyl-1-propan-2-ylsulfonylbutan-2-yl]-2-oxopiperidin-3-yl]acetic acid	1908064: Inhibition of human MDM2/p53 interaction by HTRF based biochemical assay	ic50	0.0006	uM
4-[[(2’R,3S,3’R,5’S)-6-chloro-3’-(3-chlorophenyl)-5’-(2,2-dimethylpropyl)-1’-ethylspiro[1,2-dihydroindole-3,4’-pyrrolidine]-2’-carbonyl]amino]-3-methoxybenzoic acid	2075718: Inhibition of MDM2/p53 (unknown origin) interaction by fluorescence polarization assay	ki	0.0007	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-(6-chloro-2-pyridinyl)propyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	1188939: Inhibition of human MDM2 (1-188 aa) -p53 (1-83 aa) interaction expressed in Escherichia coli after 18 hrs by HTRF assay	ic50	0.0007	uM
4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide	2074070: Binding affinity to MDM4/p53 interaction (unknown origin) assessed as inhibition constant	ki	0.0008	uM
3-[4-(5-chloro-3-pyridinyl)-3-[(4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]imidazo[4,5-c]pyridin-6-yl]-4H-1,2,4-oxadiazol-5-one	1807775: Inhibition of N-terminal thioredoxin-His6 tagged HDM2 (17 to 125 residues)/p53 protein-protein interaction (unknown origin) incubated for 2 hrs by TR-FRET assay	ic50	0.0008	uM
tert-butyl (2S)-2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-3-(2H-tetrazol-5-ylmethyl)piperidin-1-yl]butanoate	706601: Inhibition of human MDM2-p53 interaction after 18 hrs by HTRF assay	ic50	0.0009	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-[(1S)-1-[(2S)-oxolan-2-yl]propyl]piperidin-3-yl]acetic acid	1188939: Inhibition of human MDM2 (1-188 aa) -p53 (1-83 aa) interaction expressed in Escherichia coli after 18 hrs by HTRF assay	ic50	0.0010	uM
(2S)-3-[4-(2,4-difluorophenyl)triazol-1-yl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid	1928056: Inhibition of human DM2-p53 protein-protein interaction by fluorescence anisotropy analysis	ic50	0.0010	uM
4-[(3S,5’S,7’R,7’aR)-6-chloro-7’-(3-chlorophenyl)-5’-[(1-methylcyclobutyl)methyl]-1’-oxospiro[1,2-dihydroindole-3,6’-3,5,7,7a-tetrahydropyrrolo[1,2-c]imidazole]-2’-yl]-3-methoxybenzoic acid	2075718: Inhibition of MDM2/p53 (unknown origin) interaction by fluorescence polarization assay	ki	0.0010	uM
4-[(3S,5’S,7’R,7’aR)-6-chloro-7’-(3-chlorophenyl)-5’-(2,2-dimethylbutyl)-1’-oxospiro[1,2-dihydroindole-3,6’-3,5,7,7a-tetrahydropyrrolo[1,2-c]imidazole]-2’-yl]-3-methoxybenzoic acid	2075718: Inhibition of MDM2/p53 (unknown origin) interaction by fluorescence polarization assay	ki	0.0010	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2S,3S)-2-hydroxypentan-3-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	1188939: Inhibition of human MDM2 (1-188 aa) -p53 (1-83 aa) interaction expressed in Escherichia coli after 18 hrs by HTRF assay	ic50	0.0010	uM
(1S)-1-(4-chlorophenyl)-2-[4-[[4-(dimethylamino)cyclohexyl]methyl-methylamino]phenyl]-6-methoxy-7-propan-2-yloxy-1,4-dihydroisoquinolin-3-one	1238620: Inhibition of MDM2/p53 interaction (unknown origin) using biotinylated MDM2 and Cy5-p53 (18 to 26 amino acids) by TR-FRET assay	ic50	0.0011	uM
3-[4-(5-chloro-3-pyridinyl)-2-[cyclopropyl(ethoxy)methyl]-3-[(4-methylcyclohexyl)methyl]imidazo[4,5-c]pyridin-6-yl]-4H-1,2,4-oxadiazol-5-one	1807775: Inhibition of N-terminal thioredoxin-His6 tagged HDM2 (17 to 125 residues)/p53 protein-protein interaction (unknown origin) incubated for 2 hrs by TR-FRET assay	ic50	0.0012	uM
N-[(3S,4R,5R,6R)-2-[4-(2,4-difluorophenyl)triazol-1-yl]-4,5-bis(phenylmethoxy)-6-(phenylmethoxymethyl)oxan-3-yl]acetamide	1928056: Inhibition of human DM2-p53 protein-protein interaction by fluorescence anisotropy analysis	ic50	0.0012	uM
4-[(3S,5’S,7’R,7’aR)-6-chloro-7’-(3-chlorophenyl)-5’-(2,2-dimethylpropyl)-1’-oxospiro[1,2-dihydropyrrolo[3,2-b]pyridine-3,6’-3,5,7,7a-tetrahydropyrrolo[1,2-c]imidazole]-2’-yl]-3-methoxybenzoic acid	2075718: Inhibition of MDM2/p53 (unknown origin) interaction by fluorescence polarization assay	ki	0.0012	uM
4-[(3S,5’S,7’R,7’aR)-6-chloro-5’-(2,2-dimethylpropyl)-7’-(3-fluorophenyl)-1’-oxospiro[1,2-dihydroindole-3,6’-3,5,7,7a-tetrahydropyrrolo[1,2-c]imidazole]-2’-yl]-3-methoxybenzoic acid	2075718: Inhibition of MDM2/p53 (unknown origin) interaction by fluorescence polarization assay	ki	0.0012	uM
4-[(3S,5’S,7’R,7’aR)-6-chloro-7’-(3-chlorophenyl)-5’-(2-ethyl-2-methylbutyl)-1’-oxospiro[1,2-dihydroindole-3,6’-3,5,7,7a-tetrahydropyrrolo[1,2-c]imidazole]-2’-yl]-3-methoxybenzoic acid	2075718: Inhibition of MDM2/p53 (unknown origin) interaction by fluorescence polarization assay	ki	0.0012	uM
3-[4-(5-chloro-3-pyridinyl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(4-methylcyclohexyl)methyl]imidazo[4,5-c]pyridin-6-yl]-4H-1,2,4-oxadiazol-5-one	1807775: Inhibition of N-terminal thioredoxin-His6 tagged HDM2 (17 to 125 residues)/p53 protein-protein interaction (unknown origin) incubated for 2 hrs by TR-FRET assay	ic50	0.0013	uM
3-[6-(3-chlorophenyl)-7-[(4-methylcyclohexyl)methyl]-8-[(3R)-3-phenylmorpholin-4-yl]purin-2-yl]-4H-1,2,4-oxadiazol-5-one	1807775: Inhibition of N-terminal thioredoxin-His6 tagged HDM2 (17 to 125 residues)/p53 protein-protein interaction (unknown origin) incubated for 2 hrs by TR-FRET assay	ic50	0.0013	uM
(1S)-1-(3-fluorophenyl)-1-[1-(phenylsulfanylmethyl)triazol-4-yl]ethanol	1928056: Inhibition of human DM2-p53 protein-protein interaction by fluorescence anisotropy analysis	ic50	0.0013	uM
4-[(3S,5’S,7’R,7’aR)-6-chloro-7’-(3-chlorophenyl)-1’-oxo-5’-(2,2,3-trimethylbutyl)spiro[1,2-dihydroindole-3,6’-3,5,7,7a-tetrahydropyrrolo[1,2-c]imidazole]-2’-yl]-3-methoxybenzoic acid	2075718: Inhibition of MDM2/p53 (unknown origin) interaction by fluorescence polarization assay	ki	0.0013	uM
(2’R,3R,3’S,5’S)-6-chloro-3’-(3-chloro-2-fluorophenyl)-5’-(2,2-dimethylpropyl)-N-(4-hydroxycyclohexyl)-2-oxospiro[1H-indole-3,4’-pyrrolidine]-2’-carboxamide	2075718: Inhibition of MDM2/p53 (unknown origin) interaction by fluorescence polarization assay	ki	0.0013	uM
5-[6-[[(1R)-1-cyclobutylethyl]amino]-7-[(4-methylcyclohexyl)methyl]-8-[(3R)-3-phenylmorpholin-4-yl]purin-2-yl]-2-methyl-4H-1,2,4-triazol-3-one	1807775: Inhibition of N-terminal thioredoxin-His6 tagged HDM2 (17 to 125 residues)/p53 protein-protein interaction (unknown origin) incubated for 2 hrs by TR-FRET assay	ic50	0.0015	uM
4-(2,4-difluorophenyl)-1-(phenylsulfanylmethyl)triazole	1928056: Inhibition of human DM2-p53 protein-protein interaction by fluorescence anisotropy analysis	ic50	0.0015	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-[(1S)-1-pyridin-3-ylpropyl]piperidin-3-yl]acetic acid	1188939: Inhibition of human MDM2 (1-188 aa) -p53 (1-83 aa) interaction expressed in Escherichia coli after 18 hrs by HTRF assay	ic50	0.0015	uM
6-[[(1R)-1-cyclobutylethyl]amino]-8-[[(1R)-2-hydroxy-1-phenylethyl]amino]-7-[[4-(trifluoromethyl)phenyl]methyl]purine-2-carboxylic acid	1807775: Inhibition of N-terminal thioredoxin-His6 tagged HDM2 (17 to 125 residues)/p53 protein-protein interaction (unknown origin) incubated for 2 hrs by TR-FRET assay	ic50	0.0015	uM
3-[4-(5-chloro-3-pyridinyl)-2-(1-methoxypropan-2-yl)-3-[(1R)-1-(4-methylcyclohexyl)ethyl]imidazo[4,5-c]pyridin-6-yl]-4H-1,2,4-oxadiazol-5-one	1807775: Inhibition of N-terminal thioredoxin-His6 tagged HDM2 (17 to 125 residues)/p53 protein-protein interaction (unknown origin) incubated for 2 hrs by TR-FRET assay	ic50	0.0016	uM
(1S)-1-(4-chlorophenyl)-2-[6-[[4-(dimethylamino)cyclohexyl]methyl-methylamino]-3-pyridinyl]-6-methoxy-7-propan-2-yloxy-1,4-dihydroisoquinolin-3-one	1238620: Inhibition of MDM2/p53 interaction (unknown origin) using biotinylated MDM2 and Cy5-p53 (18 to 26 amino acids) by TR-FRET assay	ic50	0.0016	uM
(1S)-1-(4-chlorophenyl)-6-methoxy-2-[4-[methyl-[[4-(3-oxopiperazin-1-yl)cyclohexyl]methyl]amino]phenyl]-7-propan-2-yloxy-1,4-dihydroisoquinolin-3-one	1238620: Inhibition of MDM2/p53 interaction (unknown origin) using biotinylated MDM2 and Cy5-p53 (18 to 26 amino acids) by TR-FRET assay	ic50	0.0016	uM
(1S)-1-(4-chlorophenyl)-6-methoxy-2-[4-[methyl-[[4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl]methyl]amino]phenyl]-7-propan-2-yloxy-1,4-dihydroisoquinolin-3-one	1238620: Inhibition of MDM2/p53 interaction (unknown origin) using biotinylated MDM2 and Cy5-p53 (18 to 26 amino acids) by TR-FRET assay	ic50	0.0017	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2S)-1-hydroxybutan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	706601: Inhibition of human MDM2-p53 interaction after 18 hrs by HTRF assay	ic50	0.0017	uM
(1S)-1-(4-chlorophenyl)-6-methoxy-2-[4-[methyl-[[4-(4-oxoimidazolidin-1-yl)cyclohexyl]methyl]amino]phenyl]-7-propan-2-yloxy-1,4-dihydroisoquinolin-3-one	1238620: Inhibition of MDM2/p53 interaction (unknown origin) using biotinylated MDM2 and Cy5-p53 (18 to 26 amino acids) by TR-FRET assay	ic50	0.0017	uM
3-[4-(5-chloro-3-pyridinyl)-2-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-3-[(4-methylcyclohexyl)methyl]imidazo[4,5-c]pyridin-6-yl]-4H-1,2,4-oxadiazol-5-one	1807775: Inhibition of N-terminal thioredoxin-His6 tagged HDM2 (17 to 125 residues)/p53 protein-protein interaction (unknown origin) incubated for 2 hrs by TR-FRET assay	ic50	0.0018	uM
4-[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino]-2-methoxybenzoic acid	2075718: Inhibition of MDM2/p53 (unknown origin) interaction by fluorescence polarization assay	ki	0.0018	uM
tert-butyl (2S)-2-[(2S,3R,5R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxo-5-(2H-tetrazol-5-ylmethyl)piperidin-1-yl]butanoate	706601: Inhibition of human MDM2-p53 interaction after 18 hrs by HTRF assay	ic50	0.0018	uM
6-[[(1R)-1-cyclobutylethyl]amino]-8-[(3R)-3-phenylmorpholin-4-yl]-7-[[4-(trifluoromethyl)phenyl]methyl]purine-2-carboxylic acid	1807775: Inhibition of N-terminal thioredoxin-His6 tagged HDM2 (17 to 125 residues)/p53 protein-protein interaction (unknown origin) incubated for 2 hrs by TR-FRET assay	ic50	0.0018	uM
(1S)-7-[(2R)-butan-2-yl]oxy-1-(4-chlorophenyl)-2-[4-[[4-(dimethylamino)cyclohexyl]methyl-methylamino]phenyl]-6-methoxy-1,4-dihydroisoquinolin-3-one	1238620: Inhibition of MDM2/p53 interaction (unknown origin) using biotinylated MDM2 and Cy5-p53 (18 to 26 amino acids) by TR-FRET assay	ic50	0.0019	uM
2-[(3S,3’aS,6’S,6’aS)-6-chloro-6’-(3-chloro-2-fluorophenyl)-4’-[(3-ethoxyphenyl)methyl]-2-oxospiro[1H-indole-3,5’-3,3a,6,6a-tetrahydro-2H-pyrrolo[3,2-b]pyrrole]-1’-yl]acetic acid	1686430: Inhibition of GST-tagged MDM2 (amino acids 17 to 111 residues)/p53 (unknown origin) interaction incubated for 15 mins by	ic50	0.0020	uM

CTD chemical–gene interactions

1253 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Doxorubicin	increases reaction, increases phosphorylation, increases export, affects localization, decreases expression (+19 more)	86
Cisplatin	increases localization, increases phosphorylation, increases glutathionylation, increases response to substance, affects activity (+18 more)	75
Resveratrol	affects localization, affects binding, increases reaction, increases expression, affects cotreatment (+14 more)	70
Fluorouracil	affects binding, decreases reaction, increases expression, affects phosphorylation, increases phosphorylation (+14 more)	60
sodium arsenite	affects localization, increases phosphorylation, increases activity, increases stability, decreases methylation (+20 more)	54
Benzo(a)pyrene	affects methylation, affects phosphorylation, increases abundance, affects activity, affects expression (+16 more)	49
Arsenic Trioxide	affects binding, increases abundance, increases degradation, increases stability, affects reaction (+11 more)	47
Acetylcysteine	affects expression, affects cotreatment, decreases expression, decreases reaction, increases glutathionylation (+9 more)	42
Hydrogen Peroxide	increases phosphorylation, affects reaction, increases glutathionylation, decreases response to substance, increases response to substance (+10 more)	35
pifithrin	decreases activity, affects cotreatment, affects localization, increases expression, increases abundance (+8 more)	33
Etoposide	affects response to substance, decreases response to substance, increases chemical synthesis, increases response to substance, increases expression (+13 more)	32
Quercetin	affects reaction, increases activity, increases phosphorylation, decreases reaction, affects expression (+10 more)	28
Decitabine	affects localization, affects methylation, increases phosphorylation, increases reaction, decreases methylation (+12 more)	23
Particulate Matter	affects response to substance, increases methylation, decreases phosphorylation, increases phosphorylation, decreases expression (+6 more)	19
nutlin 3	increases stability, increases response to substance, decreases response to substance, decreases expression, affects cotreatment (+11 more)	17
Arsenic	increases mutagenesis, decreases expression, decreases methylation, decreases phosphorylation, increases methylation (+6 more)	17
Curcumin	increases phosphorylation, decreases reaction, increases expression, affects expression, increases activity (+4 more)	16
Tretinoin	affects expression, affects cotreatment, decreases expression, increases acetylation, affects localization (+7 more)	16
Cadmium Chloride	increases activity, affects binding, affects folding, affects localization, affects phosphorylation (+11 more)	16
bisphenol A	increases phosphorylation, increases expression, decreases expression, decreases methylation, decreases reaction	15
Caffeine	increases reaction, decreases reaction, increases phosphorylation, increases activity, increases expression (+1 more)	15
Paclitaxel	decreases response to substance, decreases expression, decreases reaction, increases expression, affects cotreatment (+1 more)	15
Estradiol	increases reaction, affects localization, affects cotreatment, increases expression, affects binding (+6 more)	14
Aflatoxin B1	increases phosphorylation, affects reaction, affects response to substance, affects cotreatment, affects expression (+7 more)	14
Bortezomib	increases expression, increases stability, increases localization, affects reaction, affects cotreatment (+8 more)	13
Cadmium	increases ubiquitination, increases activity, affects cotreatment, decreases response to substance, affects response to substance (+13 more)	13
chromium hexavalent ion	decreases reaction, increases phosphorylation, affects reaction, affects binding, increases expression (+8 more)	12
pyrazolanthrone	increases expression, decreases reaction, increases phosphorylation, increases stability, affects reaction (+5 more)	12
Capsaicin	decreases reaction, increases phosphorylation, increases degradation, increases reaction, decreases degradation (+5 more)	12
Methotrexate	decreases reaction, increases response to substance, increases acetylation, increases phosphorylation, increases activity (+5 more)	12

ChEMBL screening assays

869 unique, capped per target: 775 binding, 83 admet, 10 functional, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1040569	Binding	Inhibition of MDM2-p53 interaction in human SJSA1 cells assessed as p53 activation by Western blot	Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. — J Med Chem
CHEMBL907753	Functional	Induction of p53 dependent transcription in SJSA cell line by reporter gene assay	Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold. — J Med Chem
CHEMBL3762104	ADMET	Activation of p53 in human MCF10A cells assessed as upregulation of p21Clip1/WAF1 mRNA expression at 0.1 to 1 uM after 12 hrs by RT-PCR analysis	3-(Dipropylamino)-5-hydroxybenzofuro[2,3-f]quinazolin-1(2H)-one (DPA-HBFQ-1) plays an inhibitory role on breast cancer cell growth and progression. — Eur J Med Chem

Cellosaurus cell lines

6,100 cell lines: 5,983 cancer cell line, 32 transformed cell line, 20 spontaneously immortalized cell line, 17 induced pluripotent stem cell, 16 telomerase immortalized cell line, 13 finite cell line, 10 embryonic stem cell, 7 undefined cell line type, 2 hybrid cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0001	HEL	Cancer cell line	Male
CVCL_0002	HL-60	Cancer cell line	Female
CVCL_0004	K-562	Cancer cell line	Female
CVCL_0005	NB4	Cancer cell line	Female
CVCL_0006	THP-1	Cancer cell line	Male
CVCL_0007	U-937	Cancer cell line	Male
CVCL_0008	Daudi	Cancer cell line	Male
CVCL_0009	HDLM-2	Cancer cell line	Male
CVCL_0011	KM-3	Cancer cell line	Female
CVCL_0012	LP-1	Cancer cell line	Female

Clinical trials (associated diseases)

595 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00014638	PHASE4	COMPLETED	Letrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
NCT00022386	PHASE4	COMPLETED	Epoetin Alfa in Treating Chemotherapy-Related Anemia in Women With Stage I, Stage II, or Stage III Breast Cancer
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00030758	PHASE4	UNKNOWN	Filgrastim or Pegfilgrastim in Preventing Neutropenia in Women Receiving Chemotherapy Following Surgery for Breast Cancer
NCT00082277	PHASE4	COMPLETED	Anastrozole Biphosphonate Study in Postmenopausal Women With Hormone-Receptor-Positive Early Breast Cancer
NCT00087620	PHASE4	TERMINATED	A Study of Capecitabine In Combination With Docetaxel vs Capecitabine Followed by Docetaxel As First-Line Treatment For Metastatic Breast Cancer
NCT00121836	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) in Women With HER2-Negative Metastatic Breast Cancer
NCT00126360	PHASE4	UNKNOWN	STARS Breast Trial (Study of Anastrozole and Radiotherapy Sequencing Pilot)
NCT00127933	PHASE4	COMPLETED	XeNA Study - A Study of Xeloda (Capecitabine) in Patients With Invasive Breast Cancer
NCT00128297	PHASE4	COMPLETED	Pamidronate Administration in Breast Cancer Patients With Bone Metastases
NCT00129597	PHASE4	UNKNOWN	Effect of Ketalar to Prevent Postoperative Chronic Pain After Mastectomy
NCT00131170	PHASE4	COMPLETED	Paravertebral Block for Breast Surgery
NCT00156039	PHASE4	COMPLETED	Randomized Trial of Follow-up Strategies in Breast Cancer
NCT00160901	PHASE4	COMPLETED	Complementary Therapies for the Reduction of Side Effects During Chemotherapy for Breast Cancer
NCT00171847	PHASE4	TERMINATED	Study of the Efficacy and Safety of Letrozole Combined With Trastuzumab in Patients With Metastatic Breast Cancer
NCT00176046	PHASE4	COMPLETED	Mistletoe Extract in Early or Advanced Breast Cancer, A Feasibility Study
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00234195	PHASE4	COMPLETED	Wellbutrin XL, Major Depressive Disorder and Breast Cancer
NCT00237133	PHASE4	COMPLETED	Treatment of Locally Advanced Breast Cancer With Letrozole in Postmenopausal Women
NCT00237224	PHASE4	COMPLETED	Open Label Study of Postmenopausal Women With ER and /or PgR Positive Breast Cancer Treated With Letrozole
NCT00241046	PHASE4	TERMINATED	Letrozole in the Treatment of 1st and 2nd Line Hormone Receptor Positive Breast Cancer: Pre-therapeutic Risk Assessment
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