MDM2

Summary

MDM2 (MDM2 proto-oncogene, HGNC:6973) is a protein-coding gene on chromosome 12q15, encoding E3 ubiquitin-protein ligase Mdm2 (Q00987). E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. In precision oncology, MDM2 EXPRESSION is associated with resistance to Pemetrexed + Cisplatin in Malignant Pleural Mesothelioma (CIViC Level B); 1 further curated variant–drug associations are listed below. It is a selective cancer dependency (DepMap: 38.4% of cell lines).

This gene encodes a nuclear-localized E3 ubiquitin ligase. The encoded protein can promote tumor formation by targeting tumor suppressor proteins, such as p53, for proteasomal degradation. This gene is itself transcriptionally-regulated by p53. Overexpression or amplification of this locus is detected in a variety of different cancers. There is a pseudogene for this gene on chromosome 2. Alternative splicing results in a multitude of transcript variants, many of which may be expressed only in tumor cells.

Source: NCBI Gene 4193 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Li-Fraumeni syndrome (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 177 total — 1 likely-pathogenic
• Regional missense constraint (gnomAD): 2 of 5 regions constrained (≈26% of expected missense variation)
• GTEx eGene: eQTL in 15 tissues, sQTL in 7 (q < 0.05)
• Phenotypes (HPO): 49
• Drug target: yes — 4 via a complex or family; 14 molecules with ChEMBL bioactivity (top 2% of genes corpus-wide)
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types (inferred from mutation patterns)
• Cancer dependency (DepMap): dependent in 38.4% of screened cell lines
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.33 (highly constrained)
• MANE Select transcript: NM_002392
• Interaction hub: 5,478 STRING partners (top 1% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6973
Approved symbol	MDM2
Name	MDM2 proto-oncogene
Location	12q15
Locus type	gene with protein product
Status	Approved
Aliases	HDM2, MGC5370
Ensembl gene	ENSG00000135679
Ensembl biotype	protein_coding
OMIM	164785
Entrez	4193

Gene structure

Transcript identifiers

Ensembl transcripts: 45 — 27 protein_coding, 12 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 3 retained_intron

MANE Select: ENST00000258149

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 18, TSL 2: 3, TSL 3: 3, TSL 5: 9

ENST00000258149, ENST00000258148, ENST00000299252, ENST00000311420, ENST00000348801, ENST00000350057, ENST00000360430, ENST00000393410, ENST00000393412, ENST00000393413, ENST00000393415, ENST00000393416, ENST00000393417, ENST00000400501, ENST00000471946, ENST00000478070, ENST00000481186, ENST00000493419, ENST00000496959, ENST00000517852, ENST00000523991, ENST00000536089, ENST00000537182, ENST00000539479, ENST00000540352, ENST00000540709, ENST00000542502, ENST00000543046, ENST00000543323, ENST00000544125, ENST00000544561, ENST00000545204, ENST00000546048, ENST00000665020, ENST00000666617, ENST00000671567, ENST00000890006, ENST00000890007, ENST00000951805, ENST00000951806, ENST00001001845, ENST00001108296, ENST00001114783, ENST00001128068, ENST00001137549

RefSeq mRNA: 6 — MANE Select: NM_002392 NM_001145337, NM_001145339, NM_001145340, NM_001278462, NM_001367990, NM_002392

CCDS: CCDS61189, CCDS8986, CCDS91724

Canonical transcript exons

ENST00000258149 — 11 exons

Exon	Start	End
ENSE00001919656	68808177	68808491
ENSE00002215052	68839274	68845544
ENSE00003469551	68813554	68813628
ENSE00003476000	68836672	68836749
ENSE00003500719	68809208	68809292
ENSE00003527919	68816812	68816945
ENSE00003597511	68828771	68828931
ENSE00003645279	68835829	68835984
ENSE00003674928	68824555	68824651
ENSE00003683366	68824363	68824430
ENSE00003684852	68820325	68820374

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 98.31.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 97.0053 / max 7331.4544, expressed in 1827 samples.

Highest expression (Bgee): calcaneal tendon, adrenal tissue, ventricular zone, uterine tube, olfactory segment of nasal mucosa.

Genetic regulation across tissues (GTEx eQTL / sQTL)

MDM2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 15 tissues and its splicing (sQTL) in 7 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 22 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	1.7e-32	-0.24	12:68787127:ATTTT:A
Brain Spinal cord cervical c-1	eqtl	2.7e-08	+0.48	12:68779497:G:GGACTA
Adipose Subcutaneous	eqtl	2.3e-05	+0.11	12:68819051:T:C
Adipose Visceral Omentum	eqtl	7.0e-05	+0.16	12:68828684:C:G
Brain Cerebellar Hemisphere	eqtl	1.1e-03	-0.67	12:68815119:T:C
Nerve Tibial	eqtl	1.4e-03	+0.39	12:69705101:G:A
Esophagus Mucosa	eqtl	2.6e-03	+0.28	12:68800763:AATCT:A
Cells Cultured fibroblasts	eqtl	2.9e-03	-0.36	12:69326167:TAAG:T
Artery Tibial	eqtl	1.1e-02	+0.30	12:68808235:T:G
Breast Mammary Tissue	eqtl	1.1e-02	+0.13	12:68570882:G:A
Brain Frontal Cortex BA9	eqtl	1.4e-02	-0.59	12:68759476:G:A
Lung	eqtl	1.9e-02	+0.53	12:68822574:G:A
Cells EBV-transformed lymphocytes	eqtl	2.0e-02	+0.23	12:68739258:T:G
Esophagus Mucosa	sqtl	2.7e-02	-0.93	12:68023972:C:A
Whole Blood	sqtl	2.9e-02	-1.06	12:68273507:A:T
Stomach	sqtl	3.0e-02	-2.10	12:69784186:A:AT
Cells Cultured fibroblasts	sqtl	3.2e-02	-0.27	12:68772689:T:G
Skin Not Sun Exposed Suprapubic	sqtl	3.3e-02	-0.52	12:69612539:C:T
Brain Cerebellum	eqtl	3.4e-02	-0.19	12:68774938:T:G
Adipose Visceral Omentum	sqtl	3.9e-02	-1.56	12:68792066:T:C

FANTOM5 promoters

showing 10 of 12 alternative TSS:

Promoter ID	TPM avg	Samples expressed
126620	53.8123	1826
126622	40.0467	1608
126621	1.6264	878
126623	0.3713	139
126636	0.3511	164
126638	0.2367	73
206784	0.2190	90
126637	0.1070	22
90702	0.0962	44
126639	0.0789	15

Top tissues by expression

showing 100 of 294 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	98.31	gold quality
adrenal tissue	UBERON:0018303	97.33	gold quality
ventricular zone	UBERON:0003053	97.24	gold quality
right uterine tube	UBERON:0001302	97.08	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.95	gold quality
sural nerve	UBERON:0015488	96.79	gold quality
colonic epithelium	UBERON:0000397	96.67	gold quality
epithelium of nasopharynx	UBERON:0001951	96.34	gold quality
nasopharynx	UBERON:0001728	96.32	gold quality
tendon	UBERON:0000043	96.21	gold quality
stromal cell of endometrium	CL:0002255	96.08	gold quality
right lobe of liver	UBERON:0001114	95.77	gold quality
lower esophagus mucosa	UBERON:0035834	95.74	gold quality
ganglionic eminence	UBERON:0004023	95.72	gold quality
body of pancreas	UBERON:0001150	95.64	gold quality
right lung	UBERON:0002167	95.50	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.33	gold quality
right adrenal gland cortex	UBERON:0035827	95.33	gold quality
right adrenal gland	UBERON:0001233	94.35	gold quality
mucosa of paranasal sinus	UBERON:0005030	94.30	gold quality
left adrenal gland	UBERON:0001234	94.22	gold quality
left adrenal gland cortex	UBERON:0035825	94.17	gold quality
nerve	UBERON:0001021	94.11	gold quality
tibial nerve	UBERON:0001323	94.11	gold quality
adrenal gland	UBERON:0002369	94.05	gold quality
adrenal cortex	UBERON:0001235	94.00	gold quality
tonsil	UBERON:0002372	93.96	gold quality
upper lobe of left lung	UBERON:0008952	93.94	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.86	gold quality
vagina	UBERON:0000996	93.85	gold quality
seminal vesicle	UBERON:0000998	93.83	gold quality
mucosa of stomach	UBERON:0001199	93.82	gold quality
upper lobe of lung	UBERON:0008948	93.74	gold quality
spinal cord	UBERON:0002240	93.68	gold quality
buccal mucosa cell	CL:0002336	93.65	gold quality
adenohypophysis	UBERON:0002196	93.63	gold quality
ectocervix	UBERON:0012249	93.45	gold quality
mucosa of transverse colon	UBERON:0004991	93.40	gold quality
skin of abdomen	UBERON:0001416	93.39	gold quality
corpus callosum	UBERON:0002336	93.39	gold quality
cortical plate	UBERON:0005343	93.38	gold quality
esophagus mucosa	UBERON:0002469	93.26	gold quality
pancreas	UBERON:0001264	93.19	gold quality
metanephros cortex	UBERON:0010533	93.12	gold quality
endocervix	UBERON:0000458	92.98	gold quality
palpebral conjunctiva	UBERON:0001812	92.93	gold quality
minor salivary gland	UBERON:0001830	92.90	gold quality
granulocyte	CL:0000094	92.89	gold quality
left lobe of thyroid gland	UBERON:0001120	92.88	gold quality
skin of leg	UBERON:0001511	92.87	gold quality
omental fat pad	UBERON:0010414	92.74	gold quality
peritoneum	UBERON:0002358	92.73	gold quality
ascending aorta	UBERON:0001496	92.72	gold quality
descending thoracic aorta	UBERON:0002345	92.69	gold quality
thoracic aorta	UBERON:0001515	92.68	gold quality
right lobe of thyroid gland	UBERON:0001119	92.66	gold quality
gastrocnemius	UBERON:0001388	92.54	gold quality
cerebellar hemisphere	UBERON:0002245	92.53	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.51	gold quality
spleen	UBERON:0002106	92.47	gold quality
thyroid gland	UBERON:0002046	92.42	gold quality
amygdala	UBERON:0001876	92.40	gold quality
cerebellar cortex	UBERON:0002129	92.40	gold quality
esophagus	UBERON:0001043	92.37	gold quality
rectum	UBERON:0001052	92.34	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.29	gold quality
mouth mucosa	UBERON:0003729	92.26	gold quality
left ovary	UBERON:0002119	92.24	gold quality
putamen	UBERON:0001874	92.04	gold quality
right ovary	UBERON:0002118	92.03	gold quality
muscle of leg	UBERON:0001383	92.02	gold quality
left coronary artery	UBERON:0001626	92.02	gold quality
endometrium	UBERON:0001295	91.99	gold quality
nucleus accumbens	UBERON:0001882	91.96	gold quality
blood	UBERON:0000178	91.94	gold quality
tendon of biceps brachii	UBERON:0008188	91.94	gold quality
liver	UBERON:0002107	91.92	gold quality
bronchial epithelial cell	CL:0002328	91.88	gold quality
caudate nucleus	UBERON:0001873	91.86	gold quality
ovary	UBERON:0000992	91.85	gold quality
pituitary gland	UBERON:0000007	91.79	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.70	gold quality
prostate gland	UBERON:0002367	91.66	gold quality
adipose tissue	UBERON:0001013	91.65	gold quality
connective tissue	UBERON:0002384	91.61	gold quality
nasal cavity mucosa	UBERON:0001826	91.60	gold quality
aorta	UBERON:0000947	91.58	gold quality
Brodmann (1909) area 9	UBERON:0013540	91.55	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	91.53	gold quality
medial globus pallidus	UBERON:0002477	91.49	gold quality
stomach	UBERON:0000945	91.35	gold quality
lower esophagus	UBERON:0013473	91.34	gold quality
lower esophagus muscularis layer	UBERON:0035833	91.32	gold quality
coronary artery	UBERON:0001621	91.30	gold quality
right frontal lobe	UBERON:0002810	91.30	gold quality
zone of skin	UBERON:0000014	91.29	gold quality
body of stomach	UBERON:0001161	91.25	gold quality
body of uterus	UBERON:0009853	91.16	gold quality
saliva-secreting gland	UBERON:0001044	91.10	gold quality
female reproductive system	UBERON:0000474	90.97	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	2243.14
E-MTAB-7051	yes	1827.48
E-GEOD-98556	yes	1721.40
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Choroid plexus	tissue	88.8
Nucleus accumbens	tissue	36.6
Hippocampus	tissue	34.4	high
Corpus callosum	tissue	34.4
Postcentral gyrus	tissue	34.3
Locus coeruleus	tissue	33.4
Olfactory bulb	tissue	30.4
Bone marrow	tissue	30.0	high
Liver	tissue	28.9	high
Substantia nigra	tissue	28.1
Spinal cord	tissue	28.0
Putamen	tissue	27.8
Midbrain	tissue	26.9
Medulla oblongata	tissue	26.8
Periaqueductal gray	tissue	26.3
Hypothalamus	tissue	26.2
Amygdala	tissue	26.1
Cerebellum	tissue	26.1	high
Cerebral cortex	tissue	25.9	high
Ventral forebrain	tissue	25.9
Retrosplenial cortex	tissue	25.9
Retrosplenial and cingulate cortex	tissue	25.3
Superior colliculi	tissue	25.0
Hippocampal formation	tissue	24.7
Prefrontal cortex	tissue	24.4
Insular cortex	tissue	24.4
Thalamus	tissue	24.3
Somatosensory cortex	tissue	24.3
Basal ganglia	tissue	24.1	high
Septum	tissue	24.1
Occipital cortex	tissue	24.0
Pons	tissue	23.7
Temporal cortex	tissue	23.7
Rectum	tissue	22.7	high
Motor cortex	tissue	22.7
Entorhinal cortex	tissue	22.6
Colon	tissue	21.1	high
Placenta	tissue	17.1	high
Caudate putamen	tissue	17.0
Tonsil	tissue	16.4	high
Urinary bladder	tissue	15.7	high
Frontal cortex	tissue	15.4
Thyroid gland	tissue	15.3	high
Thymus	tissue	15.0
Lymph node	tissue	14.7	high
Lung	tissue	14.5	high
Fallopian tube	tissue	14.1	high
Retina	tissue	14.0
Adipose tissue	tissue	13.8	high
Cervix	tissue	13.3	high
Skin 1	tissue	13.1	high
Breast	tissue	13.1	high
Pancreas	tissue	12.9	high
Esophagus	tissue	12.8	high
Tongue	tissue	12.7
Skeletal muscle	tissue	12.0	high
Gallbladder	tissue	12.0	high
Smooth muscle	tissue	11.9	high
Adrenal gland	tissue	11.9	high
Prostate	tissue	11.7	high

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Temporal white matter (52.9), Corpus callosum, splenium (white matter) (51.8), Parieto-temporal junction (white matter) (51.3), Corpus callosum, genu (white matter) (49.8), Nucleus gracilis (49.5).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets:

Target	Regulation
DNMT3A	Activation
PIK3R1	Unknown

Upstream regulators (CollecTRI, top): AHR, AP1, AR, BCL11B, BCL3, BRCA1, CDKN2AIP, CREB1, CTNNBL1, DDIT3, DNMT1, E2F1, E2F2, EGR1, ELF4, ELL, EP300, ESR1, ETS1, ETS2, EWSR1, FEZF2, FLI1, FOS, FOSL2, FOXC1, FUS, GATA3, HES1, HEY1, HIF1A, HMGB2, HNF4A, HR, IRF8, JUN, JUND, LITAF, MLLT10, MLLT3

miRNA regulators (miRDB)

Targeting MDM2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 169 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3163	100.00	77.23	8605
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-551B-5P	99.96	71.28	3493

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.325, missense Z 2.58 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000258149 splits into 5 regions with different missense tolerance; 2 are missense-constrained (≈26% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
12:68,808,478–68,813,566	46 / 45.2	1.02	no
12:68,813,567–68,820,356	24 / 87.8	0.27	yes (p 9.7e-12)
12:68,820,357–68,839,309	168 / 236.6	0.71	no
12:68,839,310–68,839,688	138 / 143.7	0.96	no
12:68,839,689–68,839,846	12 / 63.8	0.19	yes (p 8.8e-11)
DepMap (CRISPR cell-line fitness): dependent in 38.4% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): Hs 852.T (-2.941), NZM3 (-2.752), MGH-ICC8 (-2.733), SLR 24 (-2.661), Malme-3M (-2.589), SJSA-1 (-2.573), SUM-102PT (-2.533), NCI-H226 (-2.531), MDST8 (-2.496), OS-RC-2 (-2.492), UACC-62 (-2.484), OVISE (-2.443), MM127 (-2.371), ZR-75-1 (-2.343), TUHR10TKB (-2.339).

Literature-anchored findings (GeneRIF, showing 40)

• evidence for distinct biological function of Trx-1 (PMID:11877442)
• dimer dissociation constants K(d) were found to be 2.2mM for reduced DmTrx and above 10mM for oxidized DmTrx as well as for the protein in the presence of reduced glutathione (PMID:15644209)
• Drosophila thioredoxin can function as an anti-aging agent and as a suppressor of Parkin-associated endothelin receptor-like receptor - and poly-glutamine-induced neurotoxicity (PMID:17301052)
• This study demonstrates that DHD localizes to the sperm nucleus to reduce its disulfide targets and is then rapidly degraded after fertilization. (PMID:27876811)
• thioredoxin DHD plays a critical role in early development to facilitate the switch from protamine-based sperm chromatin structures to the somatic nucleosomal chromatin. (PMID:28031247)
• Three classes of epigenomic regulators converge to hyperactivate the essential maternal gene deadhead within a heterochromatin mini-domain. (PMID:34982772)
• mdm2 has binding sites for phosphorylation by CK2 (PMID:10561590)
• protein interaction mapping with mouse p19ARF (PMID:11718560)
• a regulatory loop exists in which Hdm2 regulates the intracellular localization of Hdmx, and nuclear Hdmx regulates several functions of Hdm2 (ubiquitin ligase activity and p53 nuclear export). (PMID:11744695)
• higher expression in childhood leukemias with poor prognosis compared to long-term survivors (PMID:11764099)
• Normal cells may induce full-length MDM2 in response to oncogenic challenges to protect against premature cell cycle progression. MDM2 is regulated by p53 especially durnig embryogenesis where MDM2 function is inhibited. (PMID:11779693)
• findings suggest that amplification and overexpression of HMGIC and possibly MDM2 might be important genetic events that may contribute to malignant transformation of benign pleomorphic adenoma (PMID:11839563)
• absence of nucleolar or nucleoplasmic p14ARF/Hdm2 complexes in Reed Sternberg cells in Hodgkin’s lymphoma associated with expression of alternatively spliced Hdm2 transcripts (PMID:11839577)
• MDM2 overexpression correlates with favorable prognosis in human breast cancer (PMID:11859876)
• p53 ativation by nitric oxide involves down-regulation (PMID:11867628)
• role for IGF-I in the regulation of the MDM2/p53/p21 signaling pathway during DNA damage (PMID:11877395)
• Antisense of MDM2 enhance therapeutic efficiency of irinotecan in colon cancer (PMID:11894120)
• Akt enhances Mdm2-mediated ubiquitination and degradation of p53. (PMID:11923280)
• description of a novel MDM2 binding interface in p53 that plays a regulatory role in MDM2-dependent ubiquitination of p53 (PMID:11925449)
• Novel splice variants identified in pediatric rhabdomyosarcoma tumors and cell lines (PMID:11939408)
• MDMX, when exceedingly overexpressed, inhibits MDM2-mediated p53 degradation by competing with MDM2 for p53 binding (PMID:11953423)
• Cirrhotic livers reveal genetic changes in the MDM2-P14ARF system of cell cycle regulators. (PMID:11953887)
• promoter usage of mdm2 gene in human breast cancer (PMID:11956627)
• Phosphorylation of HDM2 by Akt, and protein binding (PMID:11960368)
• summarize the current understanding of post-translational modifications and their effect on conformation-based functional relationship between Mdm2 and p53 (PMID:11960904)
• MDM2 induces NF-kappaB/p65 expression transcriptionally through Sp1-binding sites; a novel, p53-independent role of MDM2 in doxorubicin resistance in acute lymphoblastic leukemia. (PMID:11964305)
• Cyclin G expression also results in reduced phosphorylation of human Hdm2 at S166. (PMID:11983168)
• p53 Stability and activity is regulated by Mdm2-mediated induction of alternative p53 translation products. (PMID:12032546)
• expression significantly correlated with favorable prognosis in esophageal squamous cell carcinoma in p53-negative patients but not p53-positive patients (PMID:12052755)
• MDM2 can inhibit PCAF-mediated p53 acetylation and activation. (PMID:12068014)
• MDM2 inhibition of p53 induces E2F1 transactivation via p21 (PMID:12080472)
• RNA polymerase III transcription can be derepressed by hdm2 (PMID:12082526)
• Multiple interacting domains contribute to p14ARF mediated inhibition of MDM2 (PMID:12085228)
• implications of phosphorylation in p53 regulation (PMID:12110584)
• Data suggest a model in which p53 directly recruits a TRRAP/acetyltransferase complex to the mdm2 gene to activate transcription. In addition, this study defines a novel mechanism utilized by the p53 tumor suppressor to regulate gene expression. (PMID:12138177)
• MDM2 has been characterized as a protein that binds to and facilitates degradation of the tumor suppressor p53. Splice variants of MDM2 transcripts have been identified in both tumors and normal tissues. (PMID:12150820)
• Hypophosphorylation of Mdm2 augments p53 stability. The degree of conservation in the central acidic domain of mouse and human Mdm2 proteins is high. (PMID:12167711)
• The candidate tumor suppressor ING1b can stabilize p53 by disrupting the regulation of p53 by MDM2. (PMID:12208736)
• MAPK as an upstream regulator of mdm2 expression (PMID:12231395)
• MDM2 is not required for p53 proteasomal degradation regulated by NADPH quinone oxidoreductase 1 (PMID:12232053)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mdm2	ENSDARG00000033443
mus_musculus	Mdm2	ENSMUSG00000020184
rattus_norvegicus	Mdm2	ENSRNOG00000006304

Paralogs (1): MDM4 (ENSG00000198625)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:96952) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 64 distinct phenotype terms.

Mouse phenotype (MP)	Records
embryonic lethality between implantation and somite formation, complete penetrance	3
decreased embryo size	2
increased tumor incidence	2
abnormal embryonic tissue morphology	2
prenatal lethality, complete penetrance	2
decreased leukocyte cell number	1
decreased neutrophil cell number	1
abnormal heart morphology	1
decreased bone marrow cell number	1
decreased granulocyte number	1
increased cell proliferation	1
decreased cell proliferation	1
increased foot pad pigmentation	1
abnormal liver morphology	1
enlarged spleen	1
spleen hypoplasia	1
decreased thymocyte number	1
decreased body weight	1
abnormal cardiovascular system physiology	1
abnormal hematopoietic system physiology	1
anemia	1
increased mortality induced by gamma-irradiation	1
abnormal gastrulation	1
thymus hypoplasia	1
hemorrhage	1

+39 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Canis lupus familiaris	P56950	95.1%	Diamond
Felis catus	Q7YRZ8	95.1%	Diamond
Equus caballus	P56951	94.5%	Diamond
Bos taurus	Q2HJ21	90.0%	Diamond
Mesocricetus auratus	Q60524	82.6%	Diamond
Arabidopsis thaliana	Q9LYW5	61.0%	Diamond
Xenopus laevis	P56273	56.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CPM	protein-coding	1368
SLC35E3	protein-coding	55508
NUP107	protein-coding	57122
TODL	ncRNA	107984471
MIR1279	ncRNA	100302182
CPSF6	protein-coding	11052

Protein

Protein identifiers

E3 ubiquitin-protein ligase Mdm2 — Q00987 (reviewed: Q00987)

Alternative names: Double minute 2 protein, Oncoprotein Mdm2, RING-type E3 ubiquitin transferase Mdm2, p53-binding protein Mdm2

All UniProt accessions (23): A0A0A8K986, A0A0A8KB88, A0A0A8KBA1, A0A0C4DFR5, A0A1B0GXJ6, A7UKX8, E5RHE2, E5RJQ0, E7EMW5, E7EPE2, Q00987, F5GWH7, F5GZB0, F5GZC3, F5H1M7, F5H4Q8, F6UXB6, G3XA89, J3KN53, J3QST1, Q96DS5, Q9H4C3, Q9H4C5

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as a ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also a component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal degradation. Ubiquitinates DCX, leading to DCX degradation and reduction of the dendritic spine density of olfactory bulb granule cells. Ubiquitinates DLG4, leading to proteasomal degradation of DLG4 which is required for AMPA receptor endocytosis. Negatively regulates NDUFS1, leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis. Binds NDUFS1 leading to its cytosolic retention rather than mitochondrial localization resulting in decreased supercomplex assembly (interactions between complex I and complex III), decreased complex I activity, ROS production, and apoptosis.

Subunit / interactions. Component of a ternary complex composed of FAM193A, MDM4 and MDM2; interaction of FAM193A with MDM4 is mediated by the MDM4 RING-type zinc finger and results in MDM4 destabilization, leading to enhanced p53/TP53 transcriptional activity. Although FAM193A interacts with MDM4 and MDM2, it does not affect formation of the p53-MDM2-MDM4 transcriptional repressor complex. Interacts with TP53/p53. Interacts with TP73/p73. Binds specifically to RNA. Can interact with RB1, E1A-associated protein EP300 and the E2F1 transcription factor. Forms a ternary complex with p53/TP53 and WWOX. Interacts with CDKN2AIP, RFWD3, USP7, PYHIN1, and RBBP6. Interacts with ARRB1 and ARRB2. Interacts with PSMA3. Found in a trimeric complex with MDM2, MDM4 and USP2. Interacts with USP2 (via N-terminus and C-terminus). Interacts with MDM4. Part of a complex with MDM2, DAXX, RASSF1 and USP7. Part of a complex with DAXX, MDM2 and USP7. Interacts directly with DAXX and USP7. Interacts (via C-terminus) with RASSF1 isoform A (via N-terminus); the interaction is independent of TP53. Interacts with APEX1; leading to its ubiquitination and degradation. Interacts with RYBP; this inhibits ubiquitination of TP53. Identified in a complex with RYBP and p53/TP53. Also a component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in regulating p53/TP53 stabilization and activity. Binds directly both p53/TP53 and TRIM28. Component of the TRIM28/KAP1-ERBB4-MDM2 complex involved in connecting growth factor responses with DNA damage. Interacts directly with both TRIM28 and ERBB4 in the complex. Interacts with DYRK2. Interacts with IGF1R. Interacts with TRIM13; the interaction ubiquitinates MDM2 leading to its proteasomal degradation. Interacts with SNAI1; this interaction promotes SNAI1 ubiquitination. Interacts with NOTCH1 (via intracellular domain). Interacts with FHIT. Interacts with RFFL and RNF34; the interaction stabilizes MDM2. Interacts with CDK5RAP3 and CDKN2A/ARF; form a ternary complex involved in regulation of p53/TP53. Interacts with MTA1. Interacts with AARB2. Interacts with MTBP. Interacts with PML. Interacts with TBRG1. Interacts (via its RanBP2-type zinc finger domain) with RPL11 in the 5S RNP complex composed of 5S RNA, RPL5 and RPL11; this interaction occurs in the nucleoplasm and negatively regulates MDM2-mediated TP53 ubiquitination and degradation. Interacts with ADGRB1; the interaction results in inhibition of MDM2-mediated ubiquitination and degradation of DLG4/PSD95, promoting DLG4 stability and regulating synaptic plasticity. Interacts with RPL23A; this interaction may promote p53/TP53 polyubiquitination. Interacts with NDUFS1. Interacts with MORN3; the interaction enhances the ubiquitination of p53/TP53. Interacts with RAD54B; RAD54B enhances the ubiquitin ligase activity of MDM2 on TP53 by promoting MDM2-MDM4 heterodimerization. (Microbial infection) Interacts with herpes virus 8 protein v-IRF4. (Microbial infection) Interacts with and ubiquitinates HIV-1 Tat.

Subcellular location. Nucleus. Nucleoplasm. Cytoplasm. Nucleolus.

Tissue specificity. Ubiquitous. Isoform Mdm2-A, isoform Mdm2-B, isoform Mdm2-C, isoform Mdm2-D, isoform Mdm2-E, isoform Mdm2-F and isoform Mdm2-G are observed in a range of cancers but absent in normal tissues.

Post-translational modifications. Phosphorylation on Ser-166 by SGK1 activates ubiquitination of p53/TP53. Phosphorylated at multiple sites near the RING domain by ATM upon DNA damage; this promotes its ubiquitination and degradation, preventing p53/TP53 degradation. Autoubiquitination leads to proteasomal degradation; resulting in p53/TP53 activation it may be regulated by SFN. Also ubiquitinated by TRIM13. ATM-phosphorylated MDM2 is ubiquitinated by the SCF(FBXO31) complex in response to genotoxic stress, promoting its degradation and p53/TP53-mediated DNA damage response. Deubiquitinated by USP2 leads to its accumulation and increases deubiquitination and degradation of p53/TP53. Deubiquitinated by USP7 leading to its stabilization.

Disease relevance. Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding. Lessel-Kubisch syndrome (LSKB) [MIM:618681] An autosomal recessive progeroid syndrome characterized by short stature, pinched facial features, prematurely gray hair, scleroderma-like skin changes, small kidneys and consecutive kidney failure, followed by severe arterial hypertension. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. Region I is sufficient for binding p53 and inhibiting its G1 arrest and apoptosis functions. It also binds p73 and E2F1. Region II contains most of a central acidic region required for interaction with ribosomal protein L5 and a putative C4-type zinc finger. The RING finger domain which coordinates two molecules of zinc interacts specifically with RNA whether or not zinc is present and mediates the heterooligomerization with MDM4. It is also essential for its ubiquitin ligase E3 activity toward p53 and itself.

Induction. By DNA damage.

Polymorphism. A polymorphism in the MDM2 promoter is associated with susceptibility to accelerated tumor formation in both hereditary and sporadic cancers [MIM:614401]. It also contributes to susceptibility to Li-Fraumeni syndrome, in patients carrying a TP53 germline mutation.

Miscellaneous. MDM2 RING finger mutations that failed to ubiquitinate p53 in vitro did not target p53 for degradation when expressed in cells. Does not interact with p53/TP53.

Similarity. Belongs to the MDM2/MDM4 family.

Isoforms (11)

UniProt ID	Names	Canonical?
Q00987-1	Mdm2	yes
Q00987-2	Mdm2-A
Q00987-3	Mdm2-A1
Q00987-4	Mdm2-B
Q00987-5	Mdm2-C
Q00987-6	Mdm2-D
Q00987-7	Mdm2-E
Q00987-8	Mdm2-alpha
Q00987-9	Mdm2-F
Q00987-10	Mdm2-G
Q00987-11	11

RefSeq proteins (6): NP_001138809, NP_001138811, NP_001138812, NP_001265391, NP_001354919, NP_002383* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR001876	Znf_RanBP2	Domain
IPR003121	SWIB_MDM2_domain	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR016495	p53_neg-reg_MDM_2/4	Family
IPR028340	Mdm2	Family
IPR036443	Znf_RanBP2_sf	Homologous_superfamily
IPR036885	SWIB_MDM2_dom_sf	Homologous_superfamily
IPR044080	MDM2_mRING-HC-C2H2C4	Domain

Pfam: PF00641, PF02201, PF13920

Enzyme classification (BRENDA)

• EC 2.3.2.27 — RING-type E3 ubiquitin transferase (BRENDA: 28 organisms, 138 substrates, 10 inhibitors, 1 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBE2W]-S-UBIQUITINYL-L-CYSTEINE	0.3014	1

UniProt features (105 total): mutagenesis site 21, strand 15, region of interest 13, modified residue 13, helix 11, splice variant 11, turn 6, binding site 4, short sequence motif 3, compositionally biased region 3, zinc finger region 2, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

showing 30 of 148 structures by resolution:

PDB	Title	Method	Resolution (Å)
6Q9L	HDM2 (17-111, WILDTYPE) COMPLEXED WITH COMPOUND 9 AT 1.13A; Structural states of Hdm2 and …	X-RAY DIFFRACTION	1.13
5C5A	Crystal Structure of HDM2 in complex with Nutlin-3a	X-RAY DIFFRACTION	1.15
6Q9O	HDM2 (17-111, WILDTYPE) COMPLEXED WITH COMPOUND 10 AT 1.21A; Structural states of Hdm2 …	X-RAY DIFFRACTION	1.21
5ZXF	The 1.25A Crystal structure of His6-tagged Mdm2 in complex with nutlin-3a	X-RAY DIFFRACTION	1.25
7QDQ	Crystal Structure of HDM2 in complex with Caylin-1	X-RAY DIFFRACTION	1.26
8F10	Structure of the MDM2 P53 binding domain in complex with H102, an all-D Helicon …	X-RAY DIFFRACTION	1.28
8P0D	Human 14-3-3 sigma in complex with human MDM2 peptide	X-RAY DIFFRACTION	1.31
5Z02	Crystal structure of HIS6-tagged Mdm2 with nutlin-3a	X-RAY DIFFRACTION	1.35
8J81	MDM2 bound with a peptoid	X-RAY DIFFRACTION	1.35
4OGN	Co-Crystal Structure of MDM2 with Inhbitor Compound 3	X-RAY DIFFRACTION	1.38
2AXI	HDM2 in complex with a beta-hairpin	X-RAY DIFFRACTION	1.4
7KJM	CRYSTAL STRUCTURE OF HUMAN MDM2 IN COMPLEX WITH D-PEPTIDE INHIBITOR (DPMI-OMEGA)	X-RAY DIFFRACTION	1.4
8F13	Structure of the MDM2 P53 binding domain in complex with H103, an all-D Helicon …	X-RAY DIFFRACTION	1.4
6SQO	Crystal structure of human MDM2 RING domain homodimer bound to UbcH5B-Ub	X-RAY DIFFRACTION	1.41
4WT2	Co-crystal Structure of MDM2 in Complex with AM-7209	X-RAY DIFFRACTION	1.42
4UE1	Structure of the stapled peptide YS-01 bound to MDM2	X-RAY DIFFRACTION	1.45
7NUS	X-RAY STRUCTURE OF HDM2/CMR19 AT 1.45A: Discovery, X-ray structure and CPP-conjugation …	X-RAY DIFFRACTION	1.45
8PWC	Crystal structure of MDM2 with Brigimadlin	X-RAY DIFFRACTION	1.46
8GCG	MDM2 bound to inhibitor	X-RAY DIFFRACTION	1.47
22IZ	Crystal structure of MDM2 in complex with St3-R staple peptide	X-RAY DIFFRACTION	1.52
4OGT	Co-Crystal Structure of MDM2 with Inhbitor Compound 46	X-RAY DIFFRACTION	1.54
7AI0	Crystal structure of human MDM2-G443T RING domain homodimer bound to UbcH5B-Ub (Crystal …	X-RAY DIFFRACTION	1.56
5OC8	HDM2 (17-111, WILD TYPE) COMPLEXED WITH NVP-HDM201 AT 1.56A	X-RAY DIFFRACTION	1.56
5LN2	Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by …	X-RAY DIFFRACTION	1.58
7BJ6	Inhibitor of MDM2-p53 Interaction	X-RAY DIFFRACTION	1.59
3LBL	Structure of human MDM2 protein in complex with Mi-63-analog	X-RAY DIFFRACTION	1.6
4HG7	Crystal Structure of an MDM2/Nutlin-3a complex	X-RAY DIFFRACTION	1.6
4UD7	Structure of the stapled peptide YS-02 bound to MDM2	X-RAY DIFFRACTION	1.6
4OBA	Co-crystal structure of MDM2 with Inhibitor Compound 4	X-RAY DIFFRACTION	1.6
3TU1	Exhaustive Fluorine Scanning towards Potent p53-MDM2 Antagonist	X-RAY DIFFRACTION	1.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q00987-F1	63.24	0.30

Antibody-complex structures (SAbDab)

1 antibodies co-crystallized with this protein: 5WTS

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Predicted intracellular proteins, Cancer-related genes, Candidate cancer biomarkers, Disease related genes, Potential drug targets, Human disease related genes, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nucleoplasm; centriolar satellite; end piece; mid piece; principal piece

Antibody reliability (HPA): IH supported · IF supported

Functional residue map

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

Ligand- & substrate-binding residues (4)

Position	Role
305	Zn(2+)
308	Zn(2+)
319	Zn(2+)
322	Zn(2+)

Post-translational modifications (13)

Type	Positions
Phosphoserine	166, 190, 240, 242, 246, 260, 262, 386, 395, 407, 425, 429
Phosphothreonine	419

Mutagenesis-validated functional residues (21)

Position	Phenotype
58	no effect on its ability to induce apoptosis.
305	no loss of ubiquitin ligase e3 activity.
374	no loss of ubiquitin ligase e3 activity.
386	in mdm2-6a mutant; abolished phosphorylation by atm and ubiquitination by the scf(fbxo31) complex; when associated with a-395, a-407 …
395	in mdm2-6a mutant; abolished phosphorylation by atm and ubiquitination by the scf(fbxo31) complex; when associated with a-386, a-407 …
407	in mdm2-6a mutant; abolished phosphorylation by atm and ubiquitination by the scf(fbxo31) complex; when associated with a-386, a-395 …
419	in mdm2-6a mutant; abolished phosphorylation by atm and ubiquitination by the scf(fbxo31) complex; when associated with a-386, a-395 …
425	in mdm2-6a mutant; abolished phosphorylation by atm and ubiquitination by the scf(fbxo31) complex; when associated with a-386, a-395 …
429	in mdm2-6a mutant; abolished phosphorylation by atm and ubiquitination by the scf(fbxo31) complex; when associated with a-386, a-395 …
438	no loss of ubiquitin ligase e3 activity.
441	fails to interact with mdm4.
449	loss of ubiquitin ligase e3 activity.
449	no substantial decrease of ubiquitin ligase e3 activity.
452	loss of ubiquitin ligase e3 activity.
455	significant decrease of ubiquitin ligase e3 activity.
457	loss of ubiquitin ligase e3 activity.
461	loss of ubiquitin ligase e3 activity.
464	loss of ubiquitin ligase e3 activity, enhances protein stability. does not inhibit interaction with apex1, but inhibits its ubiquitin …
475	loss of ubiquitin ligase e3 activity.
478	fails to interact with mdm4.
478	loss of ubiquitin ligase e3 activity.

Function

Pathways and Gene Ontology

Reactome pathways

15 curated (TAS) of 56; 6 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

56 pathways:

ID	Pathway	Evidence
R-HSA-5674400	Constitutive Signaling by AKT1 E17K in Cancer ⚕	curated
R-HSA-9725370	Signaling by ALK fusions and activated point mutants ⚕	curated
R-HSA-198323	AKT phosphorylates targets in the cytosol	curated
R-HSA-9766229	Degradation of CDH1	curated
R-HSA-2559585	Oncogene Induced Senescence	curated
R-HSA-2559580	Oxidative Stress Induced Senescence	curated
R-HSA-8941858	Regulation of RUNX3 expression and activity	curated
R-HSA-6804760	Regulation of TP53 Activity through Methylation	curated
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation	curated
R-HSA-6804757	Regulation of TP53 Degradation	curated
R-HSA-3232118	SUMOylation of transcription factors	curated
R-HSA-3232142	SUMOylation of ubiquitinylation proteins	curated
R-HSA-69541	Stabilization of p53	curated
R-HSA-399719	Trafficking of AMPA receptors	curated
R-HSA-5689880	Ub-specific processing proteases	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers ⚕	—
R-HSA-2219528	PI3K/AKT Signaling in Cancer ⚕	—
R-HSA-9700206	Signaling by ALK in cancer ⚕	—
R-HSA-418990	Adherens junctions interactions	—
R-HSA-1640170	Cell Cycle	—
R-HSA-69620	Cell Cycle Checkpoints	—
R-HSA-446728	Cell junction organization	—
R-HSA-1500931	Cell-Cell communication	—
R-HSA-421270	Cell-cell junction organization	—
R-HSA-2559583	Cellular Senescence	—
R-HSA-8953897	Cellular responses to stimuli	—
R-HSA-2262752	Cellular responses to stress	—
R-HSA-5688426	Deubiquitination	—
R-HSA-69615	G1/S DNA Damage Checkpoints	—
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-399721	Glutamate binding, activation of AMPA receptors and synaptic plasticity	—
R-HSA-9006925	Intracellular signaling by second messengers	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-9768919	NPAS4 regulates expression of target genes	electronic
R-HSA-112316	Neuronal System	—
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission	—
R-HSA-1257604	PIP3 activates AKT signaling	—
R-HSA-597592	Post-translational protein modification	—
R-HSA-73857	RNA Polymerase II Transcription	—
R-HSA-9764265	Regulation of CDH1 Expression and Function	—
R-HSA-9764561	Regulation of CDH1 Function	—
R-HSA-9764274	Regulation of Expression and Function of Type I Classical Cadherins	—
R-HSA-9759476	Regulation of Homotypic Cell-Cell Adhesion	—
R-HSA-5633007	Regulation of TP53 Activity	—
R-HSA-6806003	Regulation of TP53 Expression and Degradation	—
R-HSA-3108232	SUMO E3 ligases SUMOylate target proteins	—
R-HSA-2990846	SUMOylation	—
R-HSA-162582	Signal Transduction	—
R-HSA-9634815	Transcriptional Regulation by NPAS4	—
R-HSA-3700989	Transcriptional Regulation by TP53	—
R-HSA-8878159	Transcriptional regulation by RUNX3	—
R-HSA-112315	Transmission across Chemical Synapses	—
R-HSA-69563	p53-Dependent G1 DNA Damage Response	—
R-HSA-69580	p53-Dependent G1/S DNA damage checkpoint	—

MSigDB gene sets: 743 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, MODULE_97, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_RESPONSE_TO_IONIZING_RADIATION, BROWNE_HCMV_INFECTION_6HR_DN, MORF_FLT1, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, MORF_MSH3, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_NEGATIVE_REGULATION_OF_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_BY_P53_CLASS_MEDIATOR, BIOCARTA_ATM_PATHWAY, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, GOBP_POSITIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, HOFMANN_CELL_LYMPHOMA_UP

GO Biological Process (59): negative regulation of transcription by RNA polymerase II (GO:0000122), protein polyubiquitination (GO:0000209), ubiquitin-dependent protein catabolic process (GO:0006511), apoptotic process (GO:0006915), positive regulation of cell population proliferation (GO:0008284), response to xenobiotic stimulus (GO:0009410), response to toxic substance (GO:0009636), response to iron ion (GO:0010039), positive regulation of gene expression (GO:0010628), negative regulation of protein processing (GO:0010955), negative regulation of neuron projection development (GO:0010977), protein ubiquitination (GO:0016567), protein sumoylation (GO:0016925), DNA damage response, signal transduction by p53 class mediator (GO:0030330), protein destabilization (GO:0031648), response to magnesium ion (GO:0032026), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), protein localization to nucleus (GO:0034504), regulation of protein catabolic process (GO:0042176), response to cocaine (GO:0042220), negative regulation of apoptotic process (GO:0043066), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of DNA damage response, signal transduction by p53 class mediator (GO:0043518), establishment of protein localization (GO:0045184), response to ether (GO:0045472), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of mitotic cell cycle (GO:0045931), response to antibiotic (GO:0046677), positive regulation of protein export from nucleus (GO:0046827), response to steroid hormone (GO:0048545), positive regulation of muscle cell differentiation (GO:0051149), regulation of cell cycle (GO:0051726), protein autoubiquitination (GO:0051865), protein-containing complex assembly (GO:0065003), cellular response to hydrogen peroxide (GO:0070301), cellular response to antibiotic (GO:0071236), cellular response to vitamin B1 (GO:0071301), cellular response to alkaloid (GO:0071312), cellular response to growth factor stimulus (GO:0071363), cellular response to peptide hormone stimulus (GO:0071375), cellular response to estrogen stimulus (GO:0071391), cellular response to hypoxia (GO:0071456), cellular response to gamma radiation (GO:0071480), cellular response to UV-C (GO:0071494), fibroblast activation (GO:0072537), regulation of postsynaptic neurotransmitter receptor internalization (GO:0099149), regulation of protein catabolic process at postsynapse, modulating synaptic transmission (GO:0099576), negative regulation of signal transduction by p53 class mediator (GO:1901797), negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator (GO:1902254), response to formaldehyde (GO:1904404), positive regulation of vascular associated smooth muscle cell proliferation (GO:1904707), positive regulation of vascular associated smooth muscle cell migration (GO:1904754), amyloid fibril formation (GO:1990000), response to water-immersion restraint stress (GO:1990785), regulation of gene expression (GO:0010468), negative regulation of gene expression (GO:0010629), protein catabolic process (GO:0030163), protein-containing complex organization (GO:0043933), negative regulation of apoptotic signaling pathway (GO:2001234)

GO Molecular Function (20): p53 binding (GO:0002039), ubiquitin-protein transferase activity (GO:0004842), 5S rRNA binding (GO:0008097), zinc ion binding (GO:0008270), ligase activity (GO:0016874), SUMO transferase activity (GO:0019789), enzyme binding (GO:0019899), protein domain specific binding (GO:0019904), ubiquitin protein ligase binding (GO:0031625), receptor serine/threonine kinase binding (GO:0033612), identical protein binding (GO:0042802), peroxisome proliferator activated receptor binding (GO:0042975), ribonucleoprotein complex binding (GO:0043021), ubiquitin binding (GO:0043130), ubiquitin protein ligase activity (GO:0061630), NEDD8 ligase activity (GO:0061663), disordered domain specific binding (GO:0097718), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (11): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), endocytic vesicle membrane (GO:0030666), protein-containing complex (GO:0032991), glutamatergic synapse (GO:0098978), nuclear body (GO:0016604)

Reactome top-level categories

16 top-level categories:

Category	Pathways
Cellular Senescence	2
SUMO E3 ligases SUMOylate target proteins	2
Regulation of TP53 Activity	2
PIP3 activates AKT signaling	1
Glutamate binding, activation of AMPA receptors and synaptic plasticity	1
PI3K/AKT Signaling in Cancer	1
Deubiquitination	1
Regulation of TP53 Expression and Degradation	1
p53-Dependent G1 DNA Damage Response	1
Transcriptional regulation by RUNX3	1
Signaling by ALK in cancer	1
Regulation of CDH1 Function	1
Transcriptional Regulation by NPAS4	1
Transmission across Chemical Synapses	1
Neuronal System	1
Intracellular signaling by second messengers	1

GO top-level categories

showing 60 of 69 GO namespaces:

Category	Terms
protein binding	4
cellular anatomical structure	3
protein ubiquitination	2
response to chemical	2
response to metal ion	2
protein modification by small protein conjugation	2
ubiquitin-like protein transferase activity	2
catalytic activity	2
signaling receptor binding	2
ubiquitin-like protein ligase activity	2
nuclear lumen	2
intracellular membraneless organelle	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
modification-dependent protein catabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
protein processing	1
negative regulation of proteolysis	1
regulation of protein processing	1
negative regulation of protein maturation	1
regulation of neuron projection development	1
neuron projection development	1
negative regulation of cell projection organization	1
peptidyl-lysine modification	1
signal transduction in response to DNA damage	1
signal transduction by p53 class mediator	1
regulation of protein stability	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
protein localization to organelle	1
regulation of catabolic process	1
protein catabolic process	1
regulation of protein metabolic process	1
response to alkaloid	1
response to oxygen-containing compound	1
rRNA binding	1
transition metal ion binding	1
ubiquitin-like protein ligase binding	1
protein-containing complex binding	1
ubiquitin-like protein binding	1
ubiquitin-protein transferase activity	1
NEDD8 transferase activity	1
protein domain specific binding	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 44 of 91 annotations. The rest are phylogenetic / computational / electronic (IEA).

44 experimentally-supported GO terms:

GO term	NS	Evidence
DNA damage response, signal transduction by p53 class mediator	BP	mutant phenotype
amyloid fibril formation	BP	mutant phenotype
apoptotic process	BP	direct assay
cellular response to gamma radiation	BP	direct assay
cellular response to hypoxia	BP	expression pattern
establishment of protein localization	BP	direct assay
negative regulation of DNA damage response, signal transduction by p53 class mediator	BP	direct assay
negative regulation of DNA-templated transcription	BP	direct assay
negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator	BP	mutant phenotype
negative regulation of signal transduction by p53 class mediator	BP	direct assay
negative regulation of transcription by RNA polymerase II	BP	direct assay
positive regulation of mitotic cell cycle	BP	mutant phenotype
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	BP	direct assay
proteasome-mediated ubiquitin-dependent protein catabolic process	BP	direct assay
protein autoubiquitination	BP	mutant phenotype
protein destabilization	BP	direct assay
protein localization to nucleus	BP	direct assay
protein ubiquitination	BP	direct assay
protein-containing complex assembly	BP	direct assay
regulation of cell cycle	BP	direct assay
regulation of protein catabolic process	BP	direct assay
response to antibiotic	BP	expression pattern
ubiquitin-dependent protein catabolic process	BP	direct assay
cytoplasm	CC	direct assay
cytosol	CC	direct assay
nucleolus	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
protein-containing complex	CC	direct assay
5S rRNA binding	MF	direct assay
NEDD8 ligase activity	MF	mutant phenotype
SUMO transferase activity	MF	experiment
disordered domain specific binding	MF	physical interaction
enzyme binding	MF	physical interaction
identical protein binding	MF	physical interaction
ligase activity	MF	direct assay
p53 binding	MF	physical interaction
protein domain specific binding	MF	physical interaction
ribonucleoprotein complex binding	MF	direct assay
ubiquitin binding	MF	direct assay
ubiquitin protein ligase activity	MF	direct assay
ubiquitin protein ligase binding	MF	physical interaction
ubiquitin-protein transferase activity	MF	direct assay
zinc ion binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 5,478 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MDM2	TP53	P04637	984
MDM2	CDK4	P11802	873
MDM2	CDKN2A	P42771	873
MDM2	RPL11	P25121	858
MDM2	CDKN1A	P38936	855
MDM2	TCHP	Q9BT92	854
MDM2	CCND1	P24385	838
MDM2	ATM	Q13315	835
MDM2	RPL5	P46777	796
MDM2	GADD45A	P24522	789
MDM2	RCHY1	Q96PM5	788
MDM2	MDM4	O15151	778
MDM2	AKT1	P31749	771
MDM2	E2F1	Q01094	770
MDM2	BCL2	P10415	757

IntAct

Human interaction partners of MDM2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 192 partners by confidence:

Partner	Interaction type	MIscore	Records
TP53	physical association	1.000	98
USP7	physical association	0.970	21
MDM4	association	0.940	14
RPL11	physical association	0.920	7
DAXX	physical association	0.890	9
RPS7	physical association	0.820	14
UBC	physical association	0.820	5
AKT1	proximity	0.810	5
CDKN2A	colocalization	0.810	5
RB1	physical association	0.730	4
NUMB	physical association	0.720	6
EEF1A1	physical association	0.710	8
NCL	direct interaction	0.710	8
ARRB2	physical association	0.710	5
NPM1	physical association	0.700	4
RPS3	physical association	0.690	6
RPL5	association	0.670	4
CHEK2	physical association	0.660	6
ARRB1	physical association	0.640	2
OTUB1	physical association	0.630	3
RYBP	physical association	0.620	9
RPS27L	direct interaction	0.620	6
HIPK2	physical association	0.620	5
PML	direct interaction	0.610	11
CSNK1D	physical association	0.610	6
PSME3	physical association	0.610	5
S100A4	direct interaction	0.610	3
PLK1	phosphorylation reaction	0.600	7
RPS27	direct interaction	0.600	5
BTRC	physical association	0.590	9

BioGRID (2,718 interactions; top human partners by supporting records in a sample of 600 records): TP53 (Affinity Capture-Western; 133 records), MDM4 (Reconstituted Complex; 32 records), UBE2D1 (Reconstituted Complex; 12 records), UBE2D2 (Reconstituted Complex; 12 records), USP7 (Affinity Capture-Western; 10 records), AR (Affinity Capture-Western; 9 records), RPL11 (Affinity Capture-Western; 7 records), HIF1A (Affinity Capture-Western; 6 records), CDKN2A (Reconstituted Complex; 5 records), MAGEA2 (Reconstituted Complex; 5 records), NAT10 (Affinity Capture-Western; 5 records), RB1 (Reconstituted Complex; 5 records), SRC (Protein-peptide; 5 records), TP73 (Biochemical Activity; 5 records), HSP90B1 (Affinity Capture-Western; 4 records)

SIGNOR signaling

showing 46 of 127 signaling interactions:

A	Effect	B	Mechanism
ATM	“down-regulates activity”	MDM2	phosphorylation
AKT2	“up-regulates quantity by stabilization”	MDM2	phosphorylation
AKT2	“up-regulates activity”	MDM2	phosphorylation
AKT1	“up-regulates quantity by stabilization”	MDM2	phosphorylation
AKT1	“up-regulates activity”	MDM2	phosphorylation
ATR	“down-regulates activity”	MDM2	phosphorylation
DAPK3	“up-regulates quantity by stabilization”	MDM2	phosphorylation
AKT1	up-regulates	MDM2	phosphorylation
FHIT	down-regulates	MDM2
MAPKAPK2	“up-regulates quantity by stabilization”	MDM2	phosphorylation
MDM4	“up-regulates quantity by stabilization”	MDM2
USP7	up-regulates	MDM2	deubiquitination
BCL3	“up-regulates quantity by expression”	MDM2	“transcriptional regulation”
MDM2	down-regulates	MDM4	ubiquitination
PPM1D	up-regulates	MDM2	dephosphorylation
CDKN2AIP	“down-regulates quantity by repression”	MDM2	“transcriptional regulation”
MDM2	down-regulates	CDKN2AIP	ubiquitination
MDM2	“down-regulates quantity by repression”	CDKN1A
CSNK1D	down-regulates	MDM2	phosphorylation
NfKb-p65/p50	“up-regulates quantity by expression”	MDM2	“transcriptional regulation”
NUMB	down-regulates	MDM2	binding
ABL1	down-regulates	MDM2	phosphorylation
MDM2	down-regulates	NOTCH4	ubiquitination
PIM1	“up-regulates quantity by stabilization”	MDM2	phosphorylation
PIM1	up-regulates	MDM2	phosphorylation
ELF4	“up-regulates quantity by expression”	MDM2	“transcriptional regulation”
PLK1	up-regulates	MDM2	phosphorylation
CDKN2A	“down-regulates activity”	MDM2	relocalization
Serdemetan	down-regulates	MDM2	“chemical inhibition”
nutlin-3A	down-regulates	MDM2	“chemical inhibition”
MDM2	“down-regulates quantity by destabilization”	TP53	ubiquitination
MDM2	up-regulates	NOTCH1	ubiquitination
DAXX	up-regulates	MDM2	binding
TFAP4	“down-regulates quantity by repression”	MDM2	“transcriptional regulation”
TRIM28	“up-regulates activity”	MDM2	binding
AKT	“up-regulates activity”	MDM2	phosphorylation
PPM1D	“down-regulates quantity by destabilization”	MDM2	dephosphorylation
PPP1CC	“up-regulates quantity by stabilization”	MDM2	dephosphorylation
PPP1CA	“up-regulates quantity by stabilization”	MDM2	dephosphorylation
PPP1CB	“up-regulates quantity by stabilization”	MDM2	dephosphorylation
MDM2	“down-regulates activity”	TP73	binding
PIM	up-regulates	MDM2	phosphorylation
SRSF2	“up-regulates quantity by expression”	MDM2	“transcriptional regulation”
PP1	“up-regulates quantity by stabilization”	MDM2	dephosphorylation
PYHIN1	“down-regulates quantity by destabilization”	MDM2	binding
Ub:E2	“up-regulates activity”	MDM2	ubiquitination

Protein complexes (CORUM) (15)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

15 complexes by size:

Complex	Subunits	Members
★ ESR1-MDM2-TP53 complex	3	ESR1, MDM2, TP53
NUMB-TP53-MDM2 complex	3	MDM2, NUMB, TP53
MDM2-TP53-YY1 complex	3	MDM2, TP53, YY1
DAXX-MDM2-USP7 complex	3	USP7, DAXX, MDM2
MDM2-TFIP11-USP7 complex	3	TFIP11, USP7, MDM2
MDM2-MDM4-TP53 complex	3	MDM2, MDM4, TP53
MDM2-TP53-WWOX complex	3	MDM2, TP53, WWOX
MDM2-RSL1D1-TP53 complex	3	MDM2, RSL1D1, TP53
★ AR-HDAC1-MDM2 complex	3	AR, HDAC1, MDM2
EP300-MDM2-TP53 complex	3	MDM2, TP53, EP300
★ ERBB4-MDM2 complex, nuclear	2	MDM2, ERBB4
p53-MDM2 complex	2	MDM2, TP53
p53beta-MDM2 complex	2	MDM2, TP53
p53gamma-MDM2 complex	2	MDM2, TP53
★ ERS1-MDM2 complex	2	ESR1, MDM2

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 192 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
Stabilization of p53	7	36.8×	4e-08
MAP3K8 (TPL2)-dependent MAPK1/3 activation	6	29.5×	9e-07
Regulation of TP53 Activity through Methylation	7	26.2×	3e-07
Regulation of TP53 Degradation	12	24.2×	3e-11
Regulation of TP53 Expression and Degradation	5	17.9×	1e-04
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	7	17.8×	2e-06
Chaperone Mediated Autophagy	5	17.1×	1e-04
Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A	12	16.9×	2e-09

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of ubiquitin-dependent protein catabolic process	7	32.1×	4e-07
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	9	24.2×	4e-08
DNA damage response, signal transduction by p53 class mediator	12	23.4×	1e-10
regulation of signal transduction by p53 class mediator	8	16.6×	4e-06
cellular response to epidermal growth factor stimulus	7	12.1×	2e-04
intrinsic apoptotic signaling pathway	6	11.7×	9e-04
cellular response to UV	7	11.2×	2e-04
positive regulation of miRNA transcription	7	11.1×	3e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — LMS.

intOGen’s role is a computational inference from cohort mutation patterns and may diverge from the gene’s curated/literature role; read it alongside the evidence above.

Genetic variants

Variant evidence for MDM2: 177 ClinVar records (1 pathogenic / likely pathogenic); 3 CIViC cancer variants; 1 PharmGKB clinical annotation; 2 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	96
Likely benign	59
Benign	7

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
694663	NM_002392.6(MDM2):c.1492T>C (p.Ter498Gln)	Likely pathogenic	criteria provided, single submitter	2

Per-variant reference — Sugi Variant

Explore MDM2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 26 predictions of 1,250):

Position(s)	Effect	Δscore	Sites
12:68809203	acceptor_gain	1.0000
12:68809206–68809207	acceptor_loss	1.0000	5
12:68809293–68809294	donor_loss	1.0000	4
12:68820315	acceptor_gain	1.0000
12:68824546–68824548	acceptor_gain	1.0000	2
12:68824553–68824554	acceptor_loss	1.0000	2
12:68824652–68824653	donor_loss	1.0000	5
12:68828764	acceptor_gain	1.0000
12:68835827–68835828	acceptor_loss	1.0000	3
12:68835985	donor_loss	1.0000	2

AlphaMissense

815 missense substitutions predicted likely pathogenic (of 3,295 scored), across 182 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
H457	8	0.998	0.999
H452	8	0.996	0.999
F91	8	0.981	0.999
D80	8	0.970	0.991
D301	8	0.956	0.987
D68	8	0.951	0.989
N312	8	0.948	0.988
F86	8	0.932	0.993
F245	8	0.926	0.996
H73	8	0.923	0.977
D294	8	0.922	0.978
D243	8	0.824	0.941
D358	8	0.771	0.839
C438	7	0.999	1.000
C441	7	0.999	1.000
C464	7	0.999	1.000
C475	7	0.999	1.000
C478	7	0.999	1.000
C461	7	0.998	1.000
C319	7	0.995	0.998

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

4 prognostic cancer types:

Cancer	Prognostic	p-value
Pancreatic Adenocarcinoma (validation)	unfavorable	2.89e-05
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	4.89e-05
Pancreatic Adenocarcinoma (TCGA)	unfavorable	0.000314
Glioblastoma Multiforme (validation)	unfavorable	0.000317

Disease associations

OMIM: gene MIM:164785 | disease phenotypes: MIM:618681

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
Li-Fraumeni syndrome	Supportive	Autosomal dominant
lessel-kubisch syndrome	Limited	Unknown	2

Mondo (2): lessel-kubisch syndrome (MONDO:0032868), Li-Fraumeni syndrome (MONDO:0018875)

HPO phenotypes

49 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000089	Renal hypoplasia
HP:0000135	Hypogonadism
HP:0000160	Narrow mouth
HP:0000446	Narrow nasal bridge
HP:0000822	Hypertension
HP:0001482	Subcutaneous nodule
HP:0001620	Abnormally high-pitched voice
HP:0001909	Leukemia
HP:0002216	Premature graying of hair
HP:0002225	Sparse pubic hair
HP:0002579	Gastrointestinal dysmotility
HP:0002664	Neoplasm
HP:0002665	Lymphoma
HP:0002669	Osteosarcoma
HP:0002859	Rhabdomyosarcoma
HP:0002861	Melanoma
HP:0002863	Myelodysplasia
HP:0002885	Medulloblastoma
HP:0002888	Ependymoma
HP:0002890	Thyroid carcinoma
HP:0002894	Neoplasm of the pancreas
HP:0003002	Breast carcinoma
HP:0003003	Colon cancer
HP:0004322	Short stature
HP:0004808	Acute myeloid leukemia
HP:0006721	Acute lymphoblastic leukemia
HP:0006744	Adrenocortical carcinoma
HP:0007378	Neoplasm of the gastrointestinal tract
HP:0009592	Astrocytoma
HP:0009726	Renal neoplasm
HP:0010788	Testicular neoplasm
HP:0012125	Prostate cancer
HP:0012126	Stomach cancer
HP:0012174	Glioblastoma multiforme
HP:0012189	Hodgkin lymphoma
HP:0012211	Abnormal renal physiology
HP:0012288	Neoplasm of head and neck
HP:0012539	Non-Hodgkin lymphoma
HP:0030070	Central primitive neuroectodermal tumor
HP:0030392	Choroid plexus carcinoma
HP:0100006	Neoplasm of the central nervous system
HP:0100526	Neoplasm of the lung
HP:0100605	Neoplasm of the larynx
HP:0100615	Ovarian neoplasm
HP:0100743	Neoplasm of the rectum
HP:0100768	Choriocarcinoma
HP:0200063	Colorectal polyposis

GWAS associations

2 associations:

Study	Trait	p-value
GCST90002403_624	Red blood cell count	4e-11
GCST002515_1	Pneumoconiosis in silica exposure	2e-8

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004305	erythrocyte count

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
D016864	Li-Fraumeni Syndrome	C04.700.600; C16.320.700.600; C18.452.284.520

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (16): CHEMBL1907611 (PROTEIN-PROTEIN INTERACTION), CHEMBL3038493 (PROTEIN COMPLEX), CHEMBL3883306 (PROTEIN-PROTEIN INTERACTION), CHEMBL4106123 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523702 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523718 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523719 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523720 (PROTEIN-PROTEIN INTERACTION), CHEMBL4879538 (PROTEIN-PROTEIN INTERACTION), CHEMBL4888446 (PROTEIN COMPLEX)

Drugs acting on a complex or family that includes this protein

Curated ChEMBL mechanism-of-action drugs whose target is a protein complex or family of ≤10 members that includes MDM2 — the drug acts on the assembly or class, not necessarily on this subunit alone.

4 drugs via a complex or family:

Drug	Target (ChEMBL)	Members	Max phase
IDASANUTLIN	Tumour suppressor p53/oncoprotein Mdm2	2	3
NAVTEMADLIN	Tumour suppressor p53/oncoprotein Mdm2	2	3
ALRIZOMADLIN	Tumour suppressor p53/oncoprotein Mdm2	2	2
SIREMADLIN	Tumour suppressor p53/oncoprotein Mdm2	2	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 345,365 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

14 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL53	APOMORPHINE	4	26,040
CHEMBL803	CYTARABINE	4	205,012
CHEMBL572	NITROFURANTOIN	4	26,504
CHEMBL5314455	BRIGIMADLIN	3	10
CHEMBL2402737	IDASANUTLIN	3	1,569
CHEMBL4292264	MILADEMETAN	3	494
CHEMBL3125702	NAVTEMADLIN	3	1,157
CHEMBL4091801	ALRIZOMADLIN	2	587
CHEMBL3653256	SIREMADLIN	2	1,363
CHEMBL120563	THIRAM	2	80,036
CHEMBL3601398	CGM-097	1	948
CHEMBL3128043	PF-03758309	1	243
CHEMBL2386346	RO-5045337	1	825
CHEMBL2381408	SAR-405838	1	577

Clinical evidence (CIViC)

Drug × variant × indication, from 2 curated evidence items; also 3 prognostic. CIViC evidence level: A (validated) → B (clinical) → C (case study) → D (preclinical) → E (inferential).

2 predictive associations by evidence level:

Variant	Therapy	Indication	Effect	Level	CIViC
MDM2 EXPRESSION	Pemetrexed + Cisplatin	Malignant Pleural Mesothelioma	Resistance	CIViC B	EID827
MDM2 EXPRESSION	Navtemadlin	Ovarian Cancer	Sensitivity/Response	CIViC D	EID9852

CIViC curated variants (3)

Named clinical variants curated in CIViC for this gene (the catalogue beneath the predictive evidence above):

EXPRESSION, SNP309 (coding transcript intron variant), RS34886328 (3 prime UTR truncation).

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

1 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs1690924	Efficacy	3	Platinum compounds	Non-Small Cell Lung Carcinoma

PharmGKB variants

1 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1690924	MDM2	3	2.00	1	Platinum compounds

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

2 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs1690924	Platinum compounds	Efficacy	Genotype CC is associated with decreased overall survival when treated with Platinum compounds in people with Carcinoma, Non-Small-Cell Lung as compared to genotypes CT + TT.	PMID:29662106
rs2279744	Platinum compounds	Toxicity	Genotypes GT + TT is associated with increased severity of Drug Toxicity when treated with Platinum compounds in people with Carcinoma, Non-Small-Cell Lung as compared to genotype GG.	PMID:25482940

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — E3 ubiquitin ligase components

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
navtemadlin	Inhibition	10.35	pKd
JN122	Binding	9.15	pKi
milademetan	Binding	8.25	pIC50
ASTX295	Binding	7.03	pIC50

Binding affinities (BindingDB)

5531 measured of 5876 human assays (5902 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-(2-chlorophenyl)-5-(dimethylamino)-1,3-oxazole-4-carbonitrile	EC50	0.00186 nM
CHEMBL5187340	KI	0.002 nM
(4S)-4-(4-chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-2-[5-(hydroxymethyl)-2-methoxyphenyl]-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-6-one	IC50	0.04 nM	US-8815926: Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
3-[(4S)-4-(4-chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-6-oxo-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-2-yl]-N-(2-hydroxyethyl)-4-methoxybenzamide	IC50	0.05 nM	US-8815926: Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
4-[[2-[(3R,5R,6S)-1-[(1S)-2-tert-butylsulfonyl-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetyl]amino]-2-methoxybenzoic acid	IC50	0.0503 nM	US-8952036: Benzoic acid derivative MDM2 inhibitor for the treatment of cancer
(4S)-5-(5-chloro-1-methyl-6-oxo-3-pyridinyl)-4-(4-chlorophenyl)-2-[2-(dimethylamino)-4-methoxypyrimidin-5-yl]-3-[(2R)-1-methoxypropan-2-yl]-4H-pyrrolo[3,4-d]imidazol-6-one	IC50	0.059 nM	US-8815926: Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
CHEMBL3318761	IC50	0.059 nM
CHEMBL3318783	IC50	0.059 nM
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
(4S)-5-(5-chloro-2-oxopiperidin-3-yl)-4-(4-chlorophenyl)-2-[2-(dimethylamino)-4-methoxypyrimidin-5-yl]-3-propan-2-yl-4H-pyrrolo[3,4-c]pyrazol-6-one	IC50	0.068 nM	US-8969341: Pyrazolopyrrolidine 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
3-[4-(4-chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-6-oxo-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethylbenzamide	IC50	0.07 nM	US-8815926: Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
N-[[3-[4-(4-chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-6-oxo-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxyphenyl]methyl]acetamide	IC50	0.07 nM	US-8815926: Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
(4S)-4-(4-chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-6-one	IC50	0.07 nM	US-8815926: Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
(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
CHEMBL3318768	IC50	0.071 nM
CHEMBL3318781	IC50	0.074 nM
CHEMBL4290086	IC50	0.074 nM
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
CHEMBL3318771	IC50	0.075 nM
(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
CHEMBL3318756	IC50	0.079 nM
3-[5-(3-chloro-4-fluorophenyl)-4-(4-chlorophenyl)-6-oxo-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxybenzamide	IC50	0.08 nM	US-8815926: Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
3-[(4S)-4-(4-chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-6-oxo-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N-propan-2-ylbenzamide	IC50	0.08 nM	US-8815926: Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
N-[[3-[4-(4-chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-6-oxo-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxyphenyl]methyl]-2-hydroxyacetamide	IC50	0.08 nM	US-8815926: Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
4-[5-(3-chloro-2-fluorophenyl)-2-[2-(dimethylamino)-4-methoxypyrimidin-5-yl]-6-oxo-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-4-yl]-2-fluorobenzonitrile	IC50	0.08 nM	US-8815926: Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
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
(4S)-5-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-4-(4-chlorophenyl)-2-[2-(dimethylamino)-4-methoxypyrimidin-5-yl]-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-6-one	IC50	0.081 nM	US-8815926: Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
CHEMBL3318758	IC50	0.081 nM
CHEMBL3318762	IC50	0.086 nM
(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
CHEMBL3318782	IC50	0.088 nM
(4S)-5-(3-chloro-4-fluorophenyl)-4-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-3-[(2R)-1-methoxypropan-2-yl]-4H-pyrrolo[3,4-d]imidazol-6-one	IC50	0.089 nM	US-8815926: Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
2-[5-(aminomethyl)-2-methoxyphenyl]-4-(4-chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-6-one	IC50	0.09 nM	US-8815926: Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
5-(5-chloro-2-methylphenyl)-4-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-3-[(2R)-1-hydroxypropan-2-yl]-4H-pyrrolo[3,4-d]imidazol-6-one	IC50	0.09 nM	US-8815926: Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
3-[5-(5-chloro-2-methylphenyl)-4-(4-chlorophenyl)-6-oxo-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N-propan-2-ylbenzamide	IC50	0.09 nM	US-8815926: Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
3-[(4S)-4-(4-chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-6-oxo-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethylbenzamide	IC50	0.09 nM	US-8815926: Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
CHEMBL3318764	IC50	0.091 nM
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
4-[(4S)-5-(5-chloro-2-oxopiperidin-3-yl)-2-[2-(dimethylamino)-4-methoxypyrimidin-5-yl]-6-oxo-3-propan-2-yl-4H-pyrrolo[3,4-c]pyrazol-4-yl]benzonitrile	IC50	0.097 nM	US-8969341: Pyrazolopyrrolidine compounds
(4S)-5-(5-chloro-2-oxo-1H-pyridin-3-yl)-4-(4-chlorophenyl)-2-[2-(dimethylamino)-4-methoxypyrimidin-5-yl]-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-6-one	IC50	0.1 nM	US-8815926: Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
3-[5-(5-chloro-2-methylphenyl)-4-(4-chlorophenyl)-6-oxo-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxybenzamide	IC50	0.1 nM	US-8815926: Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
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-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-[cyclopropylsulfonyl(difluoromethyl)amino]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-(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-9296736: Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer

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
10.44	Kd	0.036	nM	CHEMBL3125527
10.42	Kd	0.038	nM	NAVTEMADLIN
10.40	IC50	0.04	nM	CHEMBL3653245
10.35	Kd	0.045	nM	NAVTEMADLIN
10.35	Ki	0.045	nM	CHEMBL4463050
10.30	IC50	0.05	nM	CHEMBL3657031
10.23	IC50	0.059	nM	CHEMBL3318761
10.23	IC50	0.059	nM	CHEMBL3318783
10.23	IC50	0.059	nM	CHEMBL3657124
10.21	IC50	0.061	nM	CHEMBL3892862
10.19	IC50	0.065	nM	CHEMBL3901716
10.17	IC50	0.068	nM	CHEMBL3691776
10.17	IC50	0.068	nM	CHEMBL3945756
10.16	IC50	0.069	nM	CHEMBL3911501
10.15	IC50	0.071	nM	CHEMBL3318768
10.15	IC50	0.07	nM	CHEMBL3639520
10.15	IC50	0.07	nM	CHEMBL3653166
10.15	IC50	0.07	nM	CHEMBL3653231
10.15	IC50	0.071	nM	CHEMBL3920430
10.13	IC50	0.074	nM	CHEMBL3318781
10.13	IC50	0.074	nM	CHEMBL4290086
10.12	IC50	0.075	nM	CHEMBL3318771
10.12	IC50	0.075	nM	CHEMBL3916525
10.11	IC50	0.078	nM	CHEMBL4110580
10.10	IC50	0.079	nM	CHEMBL3318756
10.10	IC50	0.08	nM	CHEMBL3657058
10.10	IC50	0.08	nM	CHEMBL3657040
10.10	IC50	0.08	nM	CHEMBL3657038
10.10	IC50	0.08	nM	CHEMBL3656990
10.10	IC50	0.08	nM	CHEMBL3893972
10.10	IC50	0.079	nM	CHEMBL3928320
10.10	IC50	0.08	nM	CHEMBL3653231
10.09	IC50	0.081	nM	CHEMBL3318758
10.09	IC50	0.081	nM	CHEMBL3657083
10.07	IC50	0.086	nM	CHEMBL3318762
10.06	IC50	0.088	nM	CHEMBL3318782
10.06	IC50	0.087	nM	CHEMBL3895404
10.05	IC50	0.09	nM	CHEMBL3657035
10.05	IC50	0.09	nM	CHEMBL3653173
10.05	IC50	0.09	nM	CHEMBL3653271
10.05	IC50	0.09	nM	CHEMBL3657024
10.05	IC50	0.089	nM	CHEMBL3657117
10.04	IC50	0.091	nM	CHEMBL3318764
10.03	IC50	0.094	nM	CHEMBL3937629
10.02	IC50	0.096	nM	CHEMBL3318767
10.02	IC50	0.095	nM	CHEMBL3916664
10.01	IC50	0.098	nM	CHEMBL3318760
10.01	IC50	0.097	nM	CHEMBL3691779

PubChem BioAssay actives

2454 with measured affinity, of 4615 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
2-[(3R,5S,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1R)-2-methyl-1-propan-2-ylsulfonylpropyl]-2-oxopiperidin-3-yl]acetic acid	1555419: Inhibition of p53 protein binding to MDM2 in human SJSA1 cells	ki	<0.0001	uM
4-[[(2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-(2,2-dimethylpropyl)-4-[(piperidin-4-ylmethylamino)methyl]pyrrolidine-2-carbonyl]amino]-3-methoxybenzoic acid	1908077: Displacement of 5-FAM labeled PDI peptide from MDM2 (1 to 118 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) assessed as inhibition constant incubated for 1.5 hrs by fluorescence polarization competition assay	ki	<0.0001	uM
(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
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	1075196: Binding affinity to human MDM2 by by Surface Plasmon Resonace (SPR) spectroscopy binding assay	kd	<0.0001	uM
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	1128403: Binding affinity to GST-thrombin-tagged human MDM2 (1 to 188) expressed in Escherichia coli after 1 to 2 mins by surface plasmon resonance spectroscopic analysis	kd	<0.0001	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-(ethylsulfamoyl)ethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	1184469: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay in presence of 15% human serum	ic50	0.0001	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-(propylsulfamoyl)ethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	1184469: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay in presence of 15% human serum	ic50	0.0001	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-(cyclopropylmethylsulfamoyl)ethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	1184469: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay in presence of 15% human serum	ic50	0.0001	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-(cyclopropylsulfamoyl)ethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	1184469: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay in presence of 15% human serum	ic50	0.0001	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-2-(cyclobutylsulfamoyl)-1-cyclopropylethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	1184469: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay in presence of 15% human serum	ic50	0.0001	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-2-(cyclopentylsulfamoyl)-1-cyclopropylethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	1184469: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay in presence of 15% human serum	ic50	0.0001	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-(diethylsulfamoyl)ethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	1184469: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay in presence of 15% human serum	ic50	0.0001	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-(phenylsulfamoyl)ethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	1184469: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay in presence of 15% human serum	ic50	0.0001	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-[(2-fluorophenyl)sulfamoyl]ethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	1184469: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay in presence of 15% human serum	ic50	0.0001	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-[ethyl(phenyl)sulfamoyl]ethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	1184469: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay in presence of 15% human serum	ic50	0.0001	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2S)-3,3-dimethyl-1-[(2R)-2-methylpyrrolidin-1-yl]sulfonylbutan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	1184469: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay in presence of 15% human serum	ic50	0.0001	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2S)-3,3-dimethyl-1-(4-methylpiperazin-1-yl)sulfonylbutan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	1184469: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay in presence of 15% human serum	ic50	0.0001	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2S)-3,3-dimethyl-1-piperazin-1-ylsulfonylbutan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	1184469: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay in presence of 15% human serum	ic50	0.0001	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2S)-1-[(1,1-dioxo-1,4-thiazinan-4-yl)sulfonyl]-3,3-dimethylbutan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	1184469: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay in presence of 15% human serum	ic50	0.0001	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2S)-1-[(3,3-dimethyl-2H-indol-1-yl)sulfonyl]-3,3-dimethylbutan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	1184469: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay in presence of 15% human serum	ic50	0.0001	uM
2-[(3R,5R,6S)-1-[(1S)-2-tert-butylsulfonyl-1-cyclopropylethyl]-5-(3-chloro-2-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid	1195685: Binding affinity to human GST-thrombin-tagged MDM2 ( 1 to 188 aa) assessed as inhibition of interaction with human p53 preincubated with compound for 20 mins by HTRF assay	ic50	0.0001	uM
4-[[2-[(3R,5R,6S)-1-[(1S)-2-tert-butylsulfonyl-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetyl]amino]bicyclo[2.2.2]octane-1-carboxylic acid	1195685: Binding affinity to human GST-thrombin-tagged MDM2 ( 1 to 188 aa) assessed as inhibition of interaction with human p53 preincubated with compound for 20 mins by HTRF assay	ic50	0.0001	uM
(4S)-4-(4-chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-2-(2-methoxyphenyl)-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-6-one	1421138: Inhibition of Cy5-labeled p53 derived TFSDLWKLL peptide binding to C-terminal biotin-labelled human MDM2 (2 to 188 residues) by TR-FRET assay	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
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]-3-methoxybenzoic acid	1075196: Binding affinity to human MDM2 by by Surface Plasmon Resonace (SPR) spectroscopy binding assay	kd	0.0001	uM
2-[(3R,5R,6S)-1-[(1S)-2-(tert-butylsulfamoyl)-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid	1184469: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay in presence of 15% human serum	ic50	0.0001	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-methylsulfonylethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	1075194: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay	ic50	0.0001	uM
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	1184469: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay in presence of 15% human serum	ic50	0.0001	uM
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	1075194: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay	ic50	0.0001	uM
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	1184469: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay in presence of 15% human serum	ic50	0.0001	uM
2-[(3R,5R,6S)-1-[(1S)-2-(azetidin-1-ylsulfonyl)-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid	1075194: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay	ic50	0.0001	uM
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	1075194: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay	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	1908066: Inhibition of human MDM2 by TR-FRET assay	ic50	0.0001	uM
(4S)-4-(4-chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-6-one	1421138: Inhibition of Cy5-labeled p53 derived TFSDLWKLL peptide binding to C-terminal biotin-labelled human MDM2 (2 to 188 residues) by TR-FRET assay	ic50	0.0001	uM
2-[2-[[(3R,5R,6S)-1-[(1S)-2-tert-butylsulfonyl-1-cyclopropylethyl]-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]methyl]-1,3-thiazol-5-yl]acetic acid	1129363: Binding affinity to GST-thrombin-tagged human MDM2 (1 to 188) expressed in Escherichia coli assessed as inhibition of interaction with p53 in serum free buffer incubated for 20 mins prior to p53 addition measured after 60 mins by HTRF assay	ic50	0.0001	uM
6-[[(2S,5R,6R)-4-[(1S)-2-tert-butylsulfonyl-1-cyclopropylethyl]-6-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-3-oxomorpholin-2-yl]methyl]pyridine-3-carboxylic acid	1129363: Binding affinity to GST-thrombin-tagged human MDM2 (1 to 188) expressed in Escherichia coli assessed as inhibition of interaction with p53 in serum free buffer incubated for 20 mins prior to p53 addition measured after 60 mins by HTRF assay	ic50	0.0001	uM
6-[[(3R,5R,6S)-1-[(1S)-2-tert-butylsulfonyl-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]methyl]pyridine-3-carboxylic acid	1129363: Binding affinity to GST-thrombin-tagged human MDM2 (1 to 188) expressed in Escherichia coli assessed as inhibition of interaction with p53 in serum free buffer incubated for 20 mins prior to p53 addition measured after 60 mins by HTRF assay	ic50	0.0001	uM
6-[[(2R,5R,6R)-4-[(1S)-2-tert-butylsulfonyl-1-cyclopropylethyl]-6-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-3-oxomorpholin-2-yl]methyl]pyridine-3-carboxylic acid	1129363: Binding affinity to GST-thrombin-tagged human MDM2 (1 to 188) expressed in Escherichia coli assessed as inhibition of interaction with p53 in serum free buffer incubated for 20 mins prior to p53 addition measured after 60 mins by HTRF assay	ic50	0.0001	uM
2-[(3R,5R,6S)-1-[(2S)-1-tert-butylsulfonyl-4,4,4-trifluorobutan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid	1075194: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay	ic50	0.0001	uM
2-[(3R,5R,6S)-1-[(2S)-1-tert-butylsulfonylpropan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid	1075194: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay	ic50	0.0001	uM
2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclobutyl-2-propan-2-ylsulfonylethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid	1075194: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay	ic50	0.0001	uM
2-[(3R,5R,6S)-1-[(1S)-2-tert-butylsulfonyl-1-cyclobutylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid	1075194: Binding affinity to human GST-thrombin-tagged MDM2 assessed as inhibition of interaction with human p53 after 1 hr by HTRF assay	ic50	0.0001	uM
2-[(3R,5R,6S)-1-[(1S)-2-tert-butylsulfonyl-1-cyclopropylethyl]-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid	1195685: Binding affinity to human GST-thrombin-tagged MDM2 ( 1 to 188 aa) assessed as inhibition of interaction with human p53 preincubated with compound for 20 mins by HTRF assay	ic50	0.0001	uM
4-(4-chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-2-(5-fluoro-2-methoxyphenyl)-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-6-one	1421138: Inhibition of Cy5-labeled p53 derived TFSDLWKLL peptide binding to C-terminal biotin-labelled human MDM2 (2 to 188 residues) by TR-FRET assay	ic50	0.0001	uM
(4S)-4-(4-chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-2-(2-methoxyphenyl)-3-propan-2-yl-4H-pyrrolo[3,4-c]pyrazol-6-one	1421138: Inhibition of Cy5-labeled p53 derived TFSDLWKLL peptide binding to C-terminal biotin-labelled human MDM2 (2 to 188 residues) by TR-FRET assay	ic50	0.0001	uM
2-[(3R,5R,6S)-1-[(1S)-2-tert-butylsulfonyl-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetamide	1129363: Binding affinity to GST-thrombin-tagged human MDM2 (1 to 188) expressed in Escherichia coli assessed as inhibition of interaction with p53 in serum free buffer incubated for 20 mins prior to p53 addition measured after 60 mins by HTRF assay	ic50	0.0001	uM
4-[[2-[(3R,5R,6S)-1-[(1S)-2-tert-butylsulfonyl-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetyl]amino]-2-methoxybenzoic acid	1195685: Binding affinity to human GST-thrombin-tagged MDM2 ( 1 to 188 aa) assessed as inhibition of interaction with human p53 preincubated with compound for 20 mins by HTRF assay	ic50	0.0001	uM
2-[[(3R,5R,6S)-1-[(1S)-2-tert-butylsulfonyl-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]methyl]pyridine-4-carboxylic acid	1129363: Binding affinity to GST-thrombin-tagged human MDM2 (1 to 188) expressed in Escherichia coli assessed as inhibition of interaction with p53 in serum free buffer incubated for 20 mins prior to p53 addition measured after 60 mins by HTRF assay	ic50	0.0001	uM
(3R,5R,6S)-1-[(2S)-1-tert-butylsulfonylbutan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(2H-tetrazol-5-ylmethyl)piperidin-2-one	1129363: Binding affinity to GST-thrombin-tagged human MDM2 (1 to 188) expressed in Escherichia coli assessed as inhibition of interaction with p53 in serum free buffer incubated for 20 mins prior to p53 addition measured after 60 mins by HTRF assay	ic50	0.0001	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases reaction, affects cotreatment, affects binding, affects reaction, increases phosphorylation (+4 more)	21
Doxorubicin	increases phosphorylation, increases reaction, affects reaction, affects expression, affects binding (+4 more)	12
sodium arsenite	decreases reaction, increases expression, increases reaction, affects expression, affects cotreatment (+2 more)	11
nutlin 3	increases secretion, increases reaction, decreases expression, increases response to substance, affects cotreatment (+5 more)	11
Cisplatin	affects binding, increases reaction, increases activity, increases cleavage, affects reaction (+3 more)	11
Fluorouracil	increases reaction, affects reaction, increases phosphorylation, increases expression	10
Resveratrol	decreases expression, increases reaction, affects binding, decreases reaction, affects cotreatment (+2 more)	9
Etoposide	affects binding, increases reaction, affects reaction, increases phosphorylation, decreases expression (+2 more)	9
Aflatoxin B1	affects expression, decreases methylation, increases expression	7
bisphenol A	affects expression, increases expression, increases phosphorylation, decreases reaction, affects cotreatment	5
Oxygen	decreases reaction, increases expression, increases reaction, affects cotreatment	5
Quercetin	decreases expression, decreases phosphorylation, increases expression	5
Tobacco Smoke Pollution	increases expression, decreases expression	5
arsenite	increases activity, increases degradation, increases phosphorylation, decreases reaction, increases reaction (+3 more)	4
Arsenic Trioxide	decreases expression, increases expression	4
Arsenic	increases expression, affects response to substance, decreases expression, increases abundance, affects reaction (+1 more)	4
Methotrexate	affects reaction, increases activity, increases expression, increases reaction	4
Tetrachlorodibenzodioxin	increases phosphorylation, decreases reaction, increases expression, increases reaction, decreases expression (+1 more)	4
Particulate Matter	increases expression, affects expression, decreases expression, increases abundance	4
Curcumin	decreases reaction, increases phosphorylation, decreases expression, increases expression	3
Estradiol	affects cotreatment, increases expression, decreases expression	3
Hydrogen Peroxide	decreases expression, decreases reaction, increases expression, affects binding, increases reaction	3
Valproic Acid	affects expression, decreases expression, increases expression	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	3
Cyclosporine	increases expression	3
Cadmium Chloride	decreases reaction, increases phosphorylation, affects reaction, decreases expression, decreases phosphorylation (+1 more)	3
Sirolimus	decreases expression, decreases reaction, increases phosphorylation, affects binding, increases reaction	3
thymoquinone	decreases expression	2
2,4,5,2’,5’-pentachlorobiphenyl	decreases reaction, increases phosphorylation, decreases phosphorylation	2
2,4,5,2’,4’,5’-hexachlorobiphenyl	decreases reaction, increases phosphorylation	2

ChEMBL screening assays

1007 unique, capped per target: 979 binding, 28 functional

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*

Cellosaurus cell lines

7 cell lines: 5 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D272	MDM2-RNB	Transformed cell line	Sex unspecified
CVCL_D8QI	Ubigene HCT 116 MDM2 KO	Cancer cell line	Male
CVCL_D9K3	Ubigene HEK293 MDM2 KO	Transformed cell line	Female
CVCL_E0HT	Ubigene HeLa MDM2 KO	Cancer cell line	Female
CVCL_SX67	HAP1 MDM2 (-) 1	Cancer cell line	Male
CVCL_SX68	HAP1 MDM2 (-) 2	Cancer cell line	Male
CVCL_VS52	QIMR-SB2b	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

21 trials:

NCT	Phase	Status	Title
NCT01464086	Phase 3	COMPLETED	LIFSCREEN : Evaluation of Whole Body MRI for Early Detection of Cancers in Subjects With P53 Mutation (Li-Fraumeni Syndrome)
NCT06088030	Phase 2	RECRUITING	Arsenic Trioxide Combined With Chemotherapy for the Treatment of p53-mutated Pediatric Cancer
NCT01981525	Phase 1	COMPLETED	A Pilot Study of Metformin in Patients With a Diagnosis of Li-Fraumeni Syndrome
NCT00406445	Not specified	COMPLETED	Role of p53 Gene in Metabolism Regulation in Patients With Li-Fraumeni Syndrome
NCT01143454	Not specified	RECRUITING	Characterization of Patients With Uncommon Presentations and/or Uncommon Diseases Associated With the Cardiovascular System
NCT01443468	Not specified	RECRUITING	Clinical and Genetic Studies of Li-Fraumeni Syndrome
NCT01737255	Not specified	COMPLETED	Magnetic Resonance Imaging Screening in Li Fraumeni Syndrome
NCT02289326	Not specified	COMPLETED	Biomarker Monitoring in TP53 Mutation Carriers
NCT02950987	Not specified	ACTIVE_NOT_RECRUITING	Screening With Whole Body MRI For Detection Of Primary Tumors In Children And Adults With Li-Fraumeni Syndrome (LFS) And Other Cancer Predisposition Syndromes
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03176836	Not specified	ENROLLING_BY_INVITATION	Li-Fraumeni Syndrome Imaging Study
NCT04367246	Not specified	RECRUITING	Li-Fraumeni Syndrome/TP53 Biobank
NCT04541654	Not specified	RECRUITING	Li-Fraumeni & TP53 (LiFT UP): Understanding and Progress
NCT04966923	Not specified	COMPLETED	Phenotype and Prognosis of Patients With Breast Cancer and Pathogenic Variants of TP53
NCT04982744	Not specified	RECRUITING	Registry of Li Fraumeni and Li Fraumeni Like Syndromes
NCT05126810	Not specified	RECRUITING	Willingness to Participate in a Trial Comparing Standard Genetic Counseling Versus Personalized Genetic Counseling
NCT06163365	Not specified	UNKNOWN	Inherited Cancer Early Diagnosis (ICED) Study
NCT06523582	Not specified	RECRUITING	Genetic Bases of Neuroendocrine Neoplasms in Mexican Patients
NCT06712095	Not specified	RECRUITING	Video Capsule Examination in Patients With Lynch Syndrome
NCT07005297	Not specified	NOT_YET_RECRUITING	Clinical Genetics Branch Eligibility Screening Survey
NCT07032922	Not specified	COMPLETED	Exploring How to Adapt an Evidence-Based Mindful Self-Compassion Program for Young Adults With Li-Fraumeni Syndrome

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for MDM2 across ~30M SureChEMBL compounds — explore on Sugi Predict.