NOTCH1

Summary

NOTCH1 (notch receptor 1, HGNC:7881) is a protein-coding gene on chromosome 9q34.3, encoding Neurogenic locus notch homolog protein 1 (P46531). Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. In precision oncology, NOTCH1 Mutation confers sensitivity to Prednisone in T-cell Acute Lymphoblastic Leukemia (CIViC Level C); 2 further curated variant–drug associations are listed below. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor plays a role in the development of numerous cell and tissue types. Mutations in this gene are associated with aortic valve disease, Adams-Oliver syndrome, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and head and neck squamous cell carcinoma.

Source: NCBI Gene 4851 — RefSeq curated summary.

At a glance

• Gene–disease (curated): NOTCH1-related AOS spectrum disorder (Definitive, ClinGen) — +7 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 4,454 total — 92 pathogenic, 70 likely-pathogenic
• Phenotypes (HPO): 79
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 3 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 26 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 70 downstream targets (CollecTRI)
• MANE Select transcript: NM_017617

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7881
Approved symbol	NOTCH1
Name	notch receptor 1
Location	9q34.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000148400
Ensembl biotype	protein_coding
OMIM	190198
Entrez	4851

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 7 retained_intron, 6 protein_coding, 4 nonsense_mediated_decay

ENST00000491649, ENST00000645828, ENST00000646957, ENST00000651671, ENST00000679595, ENST00000679969, ENST00000680003, ENST00000680133, ENST00000680218, ENST00000680668, ENST00000680778, ENST00000680882, ENST00000680924, ENST00000681135, ENST00000681298, ENST00000681454, ENST00000927794

RefSeq mRNA: 1 — MANE Select: NM_017617 NM_017617

CCDS: CCDS43905

Canonical transcript exons

ENST00000651671 — 34 exons

Exon	Start	End
ENSE00000985020	136522850	136523188
ENSE00000985022	136518591	136518824
ENSE00000985023	136518137	136518292
ENSE00000985024	136517752	136517937
ENSE00000985025	136517272	136517385
ENSE00000985026	136515981	136516094
ENSE00000985027	136515483	136515716
ENSE00000985028	136515290	136515400
ENSE00000985029	136514510	136514702
ENSE00000985030	136513392	136513537
ENSE00000985031	136513021	136513134
ENSE00000985032	136511152	136511271
ENSE00000985033	136510653	136510805
ENSE00000985034	136509733	136509961
ENSE00000985035	136508870	136509071
ENSE00000985036	136508232	136508385
ENSE00000985037	136507955	136508139
ENSE00000985038	136507305	136507437
ENSE00000985039	136506716	136506973
ENSE00000985040	136506527	136506639
ENSE00000985041	136505310	136505881
ENSE00000985042	136504673	136505104
ENSE00000985044	136502272	136502488
ENSE00000985045	136502001	136502088
ENSE00000985046	136501748	136501913
ENSE00000985047	136500552	136500847
ENSE00000985048	136499112	136499259
ENSE00000985049	136498899	136498996
ENSE00001042401	136523717	136523979
ENSE00001124718	136544024	136544102
ENSE00001247584	136494433	136497558
ENSE00001378880	136519443	136519565
ENSE00003681600	136503182	136503330
ENSE00003850181	136545726	136546048

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 97.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.4440 / max 435.6695, expressed in 1739 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
103176	17.1592	1703
205685	1.2848	812

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	97.85	gold quality
colonic epithelium	UBERON:0000397	93.68	gold quality
visceral pleura	UBERON:0002401	92.43	gold quality
lateral globus pallidus	UBERON:0002476	91.91	gold quality
ganglionic eminence	UBERON:0004023	91.58	gold quality
blood	UBERON:0000178	90.68	gold quality
gingival epithelium	UBERON:0001949	90.22	gold quality
gingiva	UBERON:0001828	90.00	gold quality
superficial temporal artery	UBERON:0001614	89.72	silver quality
granulocyte	CL:0000094	89.68	gold quality
mammalian vulva	UBERON:0000997	88.73	gold quality
sural nerve	UBERON:0015488	88.46	gold quality
tongue squamous epithelium	UBERON:0006919	87.94	silver quality
oral cavity	UBERON:0000167	87.80	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	87.68	gold quality
nipple	UBERON:0002030	87.58	gold quality
lower lobe of lung	UBERON:0008949	87.47	gold quality
upper lobe of lung	UBERON:0008948	87.44	gold quality
upper lobe of left lung	UBERON:0008952	87.39	gold quality
pleura	UBERON:0000977	87.36	gold quality
substantia nigra pars reticulata	UBERON:0001966	86.65	gold quality
upper leg skin	UBERON:0004262	86.65	gold quality
skin of abdomen	UBERON:0001416	86.59	gold quality
thymus	UBERON:0002370	86.41	gold quality
skin of leg	UBERON:0001511	86.35	gold quality
apex of heart	UBERON:0002098	86.35	gold quality
spleen	UBERON:0002106	86.33	gold quality
subthalamic nucleus	UBERON:0001906	86.29	gold quality
inferior olivary complex	UBERON:0002127	86.25	gold quality
zone of skin	UBERON:0000014	86.19	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	13.70
E-ANND-3	yes	11.97
E-MTAB-8205	no	242.29
E-GEOD-36552	no	32.72

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

70 targets.

Target	Regulation
ACTA2	Activation
ADAM19	Activation
ASCL1	Repression
BCL11B	Activation
BCL2	Activation
BGLAP	Repression
BMP10	Activation
BMP2	Repression
CASP3	Activation
CD44	Activation
CD8A	Repression
CDH1	Repression
CDH2	Activation
CDH5	Repression
CDKN1A	Activation
COL1A1	Activation
COL1A2	Activation
COL2A1	Activation
CR2	Activation
CSF1	Repression
DLL1	Activation
DLL4	Activation
DTX1	Activation
EFNB2	Activation
ERBB2	Activation
FABP7	Activation
GATA2	Activation
GATA3	Activation
HES1	Activation
HES5	Activation

Upstream regulators (CollecTRI, top): AHR, ALX1, AP1, AR, ATF1, ATF2, ATF3, ATF5, BCL11B, BMAL1, BMP2, CD46, CDX2, CEBPA, CEBPB, CEBPD, CGA, CREB1, CREM, CRX, CTBP2, CTNNB1, CTNNBL1, DLX4, E2F1, E2F3, EGR1, EGR3, EOMES, ESR1, ESR2, ESRRA, ESRRG, ETS2, ETV4, EZH2, FLI1, FOS, FOXA2, FOXC1

miRNA regulators (miRDB)

101 targeting NOTCH1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• expressed in human osteoblastic cells and that the expression is differentially regulated upon stimulation with osteogenic factors (PMID:11836628)
• Notch dysregulation may contribute to the neuritic dystrophy characteristically seen in Alzheimer’s disease brain. (PMID:11848684)
• Notch signaling induces rapid degradation of achaete-scute homolog 1 (PMID:11940670)
• Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma (PMID:11964309)
• Notch signalling involved in differentiation of normal adult human epidermis is altered under experimental conditions and pathologies which modify this program. (PMID:11978185)
• presenilin-1 mutation of leu 166 affects generation independent of its effect on Abeta42 production (PMID:12048239)
• acid alpha-glucosidase gene is a novel target of the Notch-1/Hes-1 signaling pathway (PMID:12065598)
• Expression of constitutively active recombinant human Notch1 proteins decreased neurite length and number after NGF treatment. (PMID:12145413)
• exerts specific protective effects against HPV-induced transformation through suppression of E6/E7 expression, and down-modulation of Notch1 expression is likely to play an important role in late stages of HPV-induced carcinogenesis (PMID:12208848)
• These data are the first to implicate the Notch pathway in the limited remyelination in multiple sclerosis. (PMID:12357247)
• Activation of Notch-1 signaling promotes the maturation of monocyte-derived dendritic cells. (PMID:12370358)
• We show here that vascular endothelial growth factor but not basic fibroblast growth factor can induce gene expression of Notch1 and Dll4, in human arterial endothelial cells. The VEGF-induced specific signaling is mediated through VEGF receptors 1 and 2 (PMID:12482957)
• Notch1 is required for transcriptional coactivator recruitment and cell growth in tumor cell lines (PMID:12509463)
• requirement for growth of SV40-transformed mesothelial cells (PMID:12527910)
• Data show that Notch1 signalling is differentially regulated in T-acute lymphoblastic leukaemia (ALL) and B-lymphoma cells. (PMID:12532332)
• inhibits p53-induced apoptosis and transactivation of PI3K-PKB/Akt pathway for HPV16 E6 and E7 cell transformation (PMID:12768030)
• The NOTCH signalling pathway regulates the basal layer of interfollicular epidermis clusters by controlling stem cell differentiation on the periphery of the clusters. (PMID:12781689)
• regulation of Notch1 activity at defined developmental windows is essential to control alphabeta versus gammadelta T-cell development and to avoid deregulated expansion of alphabeta-lineage cells. (PMID:12829602)
• The ankyrin domain of Notch1 receptor (N1IC) and zinc finger domains of YY1 were essential for the association of N1IC and YY1, which were both present in a large complex of the nucleus to suppress activity transactivated by Notch signaling (PMID:12913000)
• Notch activation directly engages gamma-secretase and subsequently leads to diminished PS1 expression, suggesting a complex set of feedback interactions following Notch activation (PMID:12960155)
• notch and erks have roles in prostate cancer bone metastases (PMID:14602722)
• Notch-1-mediated repression of activator protein-1 requires C promoter-binding factor 1 (PMID:14645224)
• activation of only Notch-1, but not Notch-2, resulted in protection of tumor cells from melphalan- and mitoxantrone-induced apoptosis. This protection was associated with up-regulation of p21(WAF/Cip) and growth inhibition of cells. (PMID:14670925)
• Notch1 signaling may participate in the development of hepatocellular carcinoma cells, affecting multiple pathways that control both cell proliferation and apoptosis. (PMID:14678992)
• Notch receptors 1&2 and their ligand Jagged1 are highly expressed in cultured and primary MM cells, suggesting Notch signaling is involved in the tight interactions between neoplastic plasma cells and their bone marrow microenvironment (PMID:14726396)
• NOTCH1 intracellular domain was found in a human malignant peripheral nerve sheath Schwann cell, indicative of ongoing Notch signaling. (PMID:14762442)
• Notch1 gene expression was decreased 5-fold in osteopontin-treated CD34+ cells (PMID:14996707)
• transcriptional transactivation by APP and Notch may involve distinct mechanisms; whereas the Notch intracellular domain directly functions in the nucleus, the AICD acts indirectly by activating Fe65 (PMID:15044485)
• Notch1 gene is involved in the differentiation and leukemogenesis in ATRA-modulated process in acute promyelocytic leukemia. (PMID:15058751)
• NMR assignment of human Notch-1 calcium binding EGF domains 11-13 (PMID:15213460)
• monoubiquitination and endocytosis of Notch are a prerequisite for its presenilin-dependent cleavage (PMID:15240571)
• upregulated in Papillomavirus-mediated cervical neoplasia and its activation is Jagged1 dependent. (PMID:15280477)
• ligand-induced reversal of controlled TMD dimerization by the Notch extracellular domain is unlikely to underlie the regulatory mechanism of intramembranous cleavage (PMID:15448134)
• more than 50% of T cell acute lymphoblastic leukemias, including tumors from all major molecular oncogenic subtypes, have activating mutations involving the extracellular heterodimerization domain and/or the C-terminal PEST domain of NOTCH1 (PMID:15472075)
• two contiguous regions of noncovalently associated extracellular impose crucial restraints that prevent premature Notch receptor activation (PMID:15485896)
• the Numb/Notch biological antagonism has a role in homeostasis of the normal mammary parenchyma and its subversion contributes to human mammary carcinogenesis (PMID:15492044)
• Notch-1 may possess tumour-promoting functions in breast cancer. (PMID:15492845)
• Notch1 inhibits the development of erythroid/megakaryocytic cells by suppressing GATA-1 activity through HES1 (PMID:15563463)
• Active gamma-secretase is present in the plasma membrane. Notch is processed at the cell surface and the majority of APP is processed by intracellular gamma-secretase (PMID:15563588)
• Notch1 fragments generated by caspase cleavage cannot inhibit apoptosis in a T-cells, confirming the abrogation of Notch1 antiapoptotic activity by caspases. (PMID:15650752)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	notch1b	ENSDARG00000052094
danio_rerio	notch1a	ENSDARG00000103554
mus_musculus	Notch1	ENSMUSG00000026923
rattus_norvegicus	Notch1	ENSRNOG00000019322

Paralogs (7): NOTCH3 (ENSG00000074181), NOTCH2 (ENSG00000134250), SNED1 (ENSG00000162804), NOTCH2NLA (ENSG00000264343), NOTCH2NLB (ENSG00000286019), NOTCH2NLR (ENSG00000286106), NOTCH2NLC (ENSG00000286219)

Protein

Protein identifiers

Neurogenic locus notch homolog protein 1 — P46531 (reviewed: P46531)

Alternative names: Translocation-associated notch protein TAN-1

All UniProt accessions (9): P46531, A0A7P0T8U6, A0A7P0T8W1, A0A7P0T9V1, A0A7P0TA56, A0A7P0TAK8, A0A7P0TB20, A0A7P0TBG2, A0A7P0Z4H9

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting. Involved in the maturation of both CD4(+) and CD8(+) cells in the thymus. Important for follicular differentiation and possibly cell fate selection within the follicle. During cerebellar development, functions as a receptor for neuronal DNER and is involved in the differentiation of Bergmann glia. Represses neuronal and myogenic differentiation. May play an essential role in postimplantation development, probably in some aspect of cell specification and/or differentiation. May be involved in mesoderm development, somite formation and neurogenesis. May enhance HIF1A function by sequestering HIF1AN away from HIF1A. Required for the THBS4 function in regulating protective astrogenesis from the subventricular zone (SVZ) niche after injury. Involved in determination of left/right symmetry by modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO).

Subunit / interactions. Heterodimer of a C-terminal fragment N(TM) and an N-terminal fragment N(EC) which are probably linked by disulfide bonds. Interacts with DNER, DTX1, DTX2 and RBPJ/RBPSUH. Also interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH1. The NOTCH1 intracellular domain interacts with SNW1; the interaction involves multimerized NOTCH1 NICD and is implicated in a formation of an intermediate preactivation complex which associates with DNA-bound CBF-1/RBPJ. The activated membrane-bound form interacts with AAK1 which promotes NOTCH1 stabilization. Forms a trimeric complex with FBXW7 and SGK1. Interacts with HIF1AN. HIF1AN negatively regulates the function of notch intracellular domain (NICD), accelerating myogenic differentiation. Interacts (via NICD) with SNAI1 (via zinc fingers); the interaction induces SNAI1 degradation via MDM2-mediated ubiquitination and inhibits SNAI1-induced cell invasion. Interacts (via NICD) with MDM2A. Interacts (via NICD) with BCL6; the interaction decreases MAML1 recruitment by NOTCH1 NICD on target genes DNA and inhibits NOTCH1 transactivation activity. Interacts with THBS4. Interacts (via the EGF-like repeat region) with CCN3 (via CTCK domain). Interacts (via EGF-like domains) with DLL4 (via N-terminal DSL and MNNL domains). Interacts with ZMIZ1. Interacts (via NICD domain) with MEGF10 (via the cytoplasmic domain). Interacts with DLL1 and JAG1. Interacts (via NICD domain) with PRAG1. Forms a complex with PRAG1, N1ICD and MAML1, in a MAML1-dependent manner. Interacts (via transmembrane region) with PSEN1; the interaction is direct. Interacts with ZFP64.

Subcellular location. Cell membrane. Late endosome membrane Nucleus.

Tissue specificity. In fetal tissues most abundant in spleen, brain stem and lung. Also present in most adult tissues where it is found mainly in lymphoid tissues.

Post-translational modifications. Synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form. Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by ADAM17 to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT). Following endocytosis, this fragment is then cleaved by one of the catalytic subunits of gamma-secretase (PSEN1 or PSEN2), to release a Notch-derived peptide containing the intracellular domain (NICD) from the membrane. Phosphorylated. O-glycosylated on the EGF-like domains. O-glucosylated at Ser-435 by KDELC1 and KDELC2. Contains both O-linked fucose and O-linked glucose in the EGF-like domains 11, 12 and 13, which are interacting with the residues on DLL4. O-linked glycosylation by GALNT11 is involved in determination of left/right symmetry: glycosylation promotes activation of NOTCH1, possibly by promoting cleavage by ADAM17, modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO). MFNG-, RFNG- and LFNG-mediated modification of O-fucose residues at specific EGF-like domains results in inhibition of its activation by JAG1 and enhancement of its activation by DLL1 via an increased binding to DLL1. Ubiquitinated. Undergoes ‘Lys-29’-linked polyubiquitination by ITCH; promotes the lysosomal degradation of non-activated internalized NOTCH1. Deubiquitination by USP12 is required for transport of internalized non-activated receptor from late endosomes to lysosomes for degradation. Monoubiquitination at Lys-1759 is required for activation by gamma-secretase cleavage, it promotes interaction with AAK1, which stabilizes it. Deubiquitination by EIF3F is necessary for nuclear import of activated Notch. Hydroxylated at Asn-1955 by HIF1AN. Hydroxylated at Asn-2022 by HIF1AN. Hydroxylation reduces affinity for HI1AN and may thus indirectly modulate negative regulation of NICD.

Disease relevance. Aortic valve disease 1 (AOVD1) [MIM:109730] A common defect in the aortic valve in which two rather than three leaflets are present. It is often associated with aortic valve calcification, stenosis and insufficiency. In extreme cases, the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome. The disease is caused by variants affecting the gene represented in this entry. Adams-Oliver syndrome 5 (AOS5) [MIM:616028] A form of Adams-Oliver syndrome, a disorder characterized by the congenital absence of skin (aplasia cutis congenita) in combination with transverse limb defects. Aplasia cutis congenita can be located anywhere on the body, but in the vast majority of the cases, it is present on the posterior parietal region where it is often associated with an underlying defect of the parietal bones. Limb abnormalities are typically limb truncation defects affecting the distal phalanges or entire digits (true ectrodactyly). Only rarely, metatarsals/metacarpals or more proximal limb structures are also affected. Apart from transverse limb defects, syndactyly, most commonly of second and third toes, can also be observed. The clinical features are highly variable and can also include cardiovascular malformations, brain abnormalities and vascular defects such as cutis marmorata and dilated scalp veins. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Interaction with PSEN1 causes partial unwinding of the transmembrane helix, facilitating access to the scissile peptide bond.

Similarity. Belongs to the NOTCH family.

RefSeq proteins (1): NP_060087* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR000800	Notch_dom	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR008297	Notch	Family
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR010660	Notch_NOD_dom	Domain
IPR011656	Notch_NODP_dom	Domain
IPR013032	EGF-like_CS	Conserved_site
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR022362	Notch_1	Family
IPR024600	Notch_C	Domain
IPR035993	Notch-like_dom_sf	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR049883	NOTCH1_EGF-like	Domain
IPR051355	Notch/Slit_guidance	Family

Pfam: PF00008, PF00023, PF00066, PF06816, PF07645, PF07684, PF12661, PF12796

UniProt features (373 total): disulfide bond 115, strand 53, glycosylation site 47, helix 39, domain 36, binding site 16, sequence conflict 13, turn 10, repeat 9, region of interest 9, sequence variant 6, compositionally biased region 4, chain 3, site 3, modified residue 3, mutagenesis site 2, topological domain 2, signal peptide 1, cross-link 1, transmembrane region 1

Structure

Experimental structures (PDB)

29 structures.

PDB	Method	Resolution (Å)
5L0R	X-RAY DIFFRACTION	1.5
9B3N	X-RAY DIFFRACTION	1.5
2F8Y	X-RAY DIFFRACTION	1.55
9B3G	X-RAY DIFFRACTION	1.55
4D0E	X-RAY DIFFRACTION	1.61
4CUD	X-RAY DIFFRACTION	1.85
2HE0	X-RAY DIFFRACTION	1.9
1YYH	X-RAY DIFFRACTION	1.9
3ETO	X-RAY DIFFRACTION	2
5UB5	X-RAY DIFFRACTION	2.09
3L95	X-RAY DIFFRACTION	2.19
4CUF	X-RAY DIFFRACTION	2.29
5FMA	X-RAY DIFFRACTION	2.46
2VJ3	X-RAY DIFFRACTION	2.6
6IDF	ELECTRON MICROSCOPY	2.7
4D0F	X-RAY DIFFRACTION	2.8
5FM9	X-RAY DIFFRACTION	2.92
4CUE	X-RAY DIFFRACTION	3
3I08	X-RAY DIFFRACTION	3.2
2F8X	X-RAY DIFFRACTION	3.25
3NBN	X-RAY DIFFRACTION	3.45
6PY8	X-RAY DIFFRACTION	3.75
3V79	X-RAY DIFFRACTION	3.85
1PB5	SOLUTION NMR
1TOZ	SOLUTION NMR
5KZO	SOLUTION NMR
8OR5	SOLUTION NMR
8ORY	SOLUTION NMR
8ORZ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P46531-F1	59.74	0.03

Antibody-complex structures (SAbDab): 1 — 3L95

Functional residue map

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

Catalytic / active sites (3): 469 (interaction with dll4); 1664–1665 (cleavage; by furin-like protease); 1710–1711 (cleavage; by adam17)

Ligand- & substrate-binding residues (16): 432; 435; 452; 453; 455; 469; 470; 490; 491; 493; 507; 508 …

Post-translational modifications (4): 1759, 1861, 1955, 2022

Disulfide bonds (115): 24–37, 31–46, 48–57, 63–74, 68–87, 89–98, 106–117, 111–127, 129–138, 144–155, 149–164, 166–175, 182–195, 189–204, 206–215, 222–233, 227–243, 245–254, 261–272, 266–281 …

Glycosylation sites (47): 458, 466, 496, 534, 609, 617, 647, 692, 722, 759, 767, 784, 797, 805, 921, 951, 959, 997, 1027, 1035 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
1728	formation of an artifactual disulfide bond with psen1.
1755–1761	loss of proteolytic cleavage by gamma-secretase.

Function

Pathways and Gene Ontology

Reactome pathways

23 pathways

ID	Pathway
R-HSA-1912399	Pre-NOTCH Processing in the Endoplasmic Reticulum
R-HSA-1912408	Pre-NOTCH Transcription and Translation
R-HSA-1912420	Pre-NOTCH Processing in Golgi
R-HSA-210744	Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells
R-HSA-2122947	NOTCH1 Intracellular Domain Regulates Transcription
R-HSA-2122948	Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2644607	Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling
R-HSA-2660826	Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant
R-HSA-2691232	Constitutive Signaling by NOTCH1 HD Domain Mutants
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-350054	Notch-HLH transcription pathway
R-HSA-5083630	Defective LFNG causes SCDO3
R-HSA-8941856	RUNX3 regulates NOTCH signaling
R-HSA-9013508	NOTCH3 Intracellular Domain Regulates Transcription
R-HSA-9013695	NOTCH4 Intracellular Domain Regulates Transcription
R-HSA-9793380	Formation of paraxial mesoderm
R-HSA-9818030	NFE2L2 regulating tumorigenic genes
R-HSA-9818749	Regulation of NFE2L2 gene expression
R-HSA-9824272	Somitogenesis
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)
R-HSA-9022699	MECP2 regulates neuronal receptors and channels
R-HSA-9725371	Nuclear events stimulated by ALK signaling in cancer

MSigDB gene sets: 1125 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, REACTOME_SIGNALING_BY_NOTCH, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_CELL_MIGRATION_INVOLVED_IN_HEART_DEVELOPMENT, LEE_NEURAL_CREST_STEM_CELL_DN, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT

GO Biological Process (194): negative regulation of transcription by RNA polymerase II (GO:0000122), luteolysis (GO:0001554), in utero embryonic development (GO:0001701), epithelial to mesenchymal transition (GO:0001837), liver development (GO:0001889), heart looping (GO:0001947), sprouting angiogenesis (GO:0002040), positive regulation of neuroblast proliferation (GO:0002052), inhibition of neuroepithelial cell differentiation (GO:0002085), inflammatory response to antigenic stimulus (GO:0002437), outflow tract morphogenesis (GO:0003151), endocardium development (GO:0003157), endocardium morphogenesis (GO:0003160), atrioventricular node development (GO:0003162), coronary vein morphogenesis (GO:0003169), aortic valve morphogenesis (GO:0003180), atrioventricular valve morphogenesis (GO:0003181), coronary sinus valve morphogenesis (GO:0003182), pulmonary valve morphogenesis (GO:0003184), mitral valve formation (GO:0003192), epithelial to mesenchymal transition involved in endocardial cushion formation (GO:0003198), endocardial cushion morphogenesis (GO:0003203), cardiac chamber formation (GO:0003207), cardiac ventricle morphogenesis (GO:0003208), cardiac atrium morphogenesis (GO:0003209), cardiac right atrium morphogenesis (GO:0003213), cardiac left ventricle morphogenesis (GO:0003214), cardiac right ventricle formation (GO:0003219), ventricular trabecula myocardium morphogenesis (GO:0003222), growth involved in heart morphogenesis (GO:0003241), obsolete negative regulation of cell proliferation involved in heart valve morphogenesis (GO:0003252), Notch signaling pathway involved in regulation of secondary heart field cardioblast proliferation (GO:0003270), cell migration involved in endocardial cushion formation (GO:0003273), negative regulation of extracellular matrix constituent secretion (GO:0003332), pericardium morphogenesis (GO:0003344), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), protein import into nucleus (GO:0006606), immune response (GO:0006955)

GO Molecular Function (13): transcription coactivator activity (GO:0003713), enzyme inhibitor activity (GO:0004857), transmembrane signaling receptor activity (GO:0004888), Notch binding (GO:0005112), calcium ion binding (GO:0005509), enzyme binding (GO:0019899), chromatin DNA binding (GO:0031490), identical protein binding (GO:0042802), transcription regulator activator activity (GO:0140537), chromatin binding (GO:0003682), protein binding (GO:0005515), signaling receptor activity (GO:0038023), metal ion binding (GO:0046872)

GO Cellular Component (25): Golgi membrane (GO:0000139), acrosomal vesicle (GO:0001669), MAML1-RBP-Jkappa- ICN1 complex (GO:0002193), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), plasma membrane (GO:0005886), adherens junction (GO:0005912), cell surface (GO:0009986), endosome membrane (GO:0010008), apical plasma membrane (GO:0016324), late endosome membrane (GO:0031902), signaling receptor complex (GO:0043235), Schaffer collateral - CA1 synapse (GO:0098685), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), endosome (GO:0005768), late endosome (GO:0005770), endoplasmic reticulum (GO:0005783), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), cell periphery (GO:0071944)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Pre-NOTCH Expression and Processing	3
Signaling by NOTCH1	2
Nuclear events mediated by NFE2L2	2
Regulation of beta-cell development	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
FBXW7 Mutants and NOTCH1 in Cancer	1
Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1
Signaling by NOTCH1 HD Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
Generic Transcription Pathway	1
Diseases associated with O-glycosylation of proteins	1
Transcriptional regulation by RUNX3	1
Signaling by NOTCH3	1
Signaling by NOTCH4	1
Gastrulation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
heart valve morphogenesis	4
anatomical structure morphogenesis	2
protein binding	2
binding	2
bounding membrane of organelle	2
protein-containing complex	2
synapse	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
female gonad development	1
ovulation cycle process	1
chordate embryonic development	1
mesenchymal cell differentiation	1
gland development	1
hepaticobiliary system development	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
angiogenesis	1
neuroblast proliferation	1
positive regulation of neurogenesis	1
regulation of neuroblast proliferation	1
positive regulation of neural precursor cell proliferation	1
regulation of anatomical structure morphogenesis	1
negative regulation of epithelial cell differentiation	1
regulation of embryonic development	1
regulation of timing of cell differentiation	1
neuroepithelial cell differentiation	1
inflammatory response	1
immune response	1
heart morphogenesis	1
heart development	1
anatomical structure development	1
endocardium development	1
cardiac conduction system development	1
cardiac muscle tissue development	1
venous blood vessel morphogenesis	1
coronary vasculature morphogenesis	1
aortic valve development	1

Protein interactions and networks

STRING

6600 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NOTCH1	RBPJ	Q06330	999
NOTCH1	MAML1	Q92585	998
NOTCH1	MAML3	Q96JK9	996
NOTCH1	MAML2	Q8IZL2	995
NOTCH1	DLL4	Q9NR61	988
NOTCH1	JAG1	P78504	988
NOTCH1	JAG2	Q9Y219	988
NOTCH1	DLL1	O00548	988
NOTCH1	DLL3	Q9NYJ7	987
NOTCH1	POSTN	Q15063	970
NOTCH1	SRRT	Q9BXP5	960
NOTCH1	SMAD3	P84022	943
NOTCH1	CTNNB1	P35222	932
NOTCH1	HIF1A	Q16665	918
NOTCH1	NUMBL	Q9Y6R0	891

IntAct

220 interactions, top by confidence:

A	B	Type	Score
NOTCH1	MAML1	psi-mi:“MI:0915”(physical association)	0.950
MAML1	NOTCH1	psi-mi:“MI:0914”(association)	0.950
MAML1	NOTCH1	psi-mi:“MI:0915”(physical association)	0.950
MAML1	NOTCH1	psi-mi:“MI:0407”(direct interaction)	0.950
RBPJ	NOTCH1	psi-mi:“MI:0914”(association)	0.910
RBPJ	NOTCH1	psi-mi:“MI:0915”(physical association)	0.910
FBXW7	NOTCH1	psi-mi:“MI:0914”(association)	0.880
FBXW7	NOTCH1	psi-mi:“MI:0407”(direct interaction)	0.880
FBXW7	NOTCH1	psi-mi:“MI:0915”(physical association)	0.880
NOTCH1	FBXW7	psi-mi:“MI:0915”(physical association)	0.880
ANKRD44	PPP6C	psi-mi:“MI:0914”(association)	0.790
NOTCH1	RBPJ	psi-mi:“MI:0914”(association)	0.740
RBPJ	NOTCH1	psi-mi:“MI:0407”(direct interaction)	0.740

BioGRID (591): NOTCH1 (Affinity Capture-Western), TGFBR1 (Affinity Capture-Western), NOTCH1 (Biochemical Activity), CBL (Affinity Capture-Western), RBPJ (Affinity Capture-Western), NOTCH1 (Affinity Capture-Western), NOTCH1 (Affinity Capture-Western), NOTCH1 (Affinity Capture-MS), NOTCH1 (Affinity Capture-MS), NOTCH1 (Synthetic Growth Defect), NOTCH1 (Proximity Label-MS), NOTCH1 (Affinity Capture-MS), NOTCH1 (Affinity Capture-MS), NOTCH1 (Affinity Capture-Western), RND3 (Affinity Capture-Western)

ESM2 similar proteins: A0A096LNW5, B8JI71, D3ZHH1, G3I6Z6, O00548, O35516, O57409, P0DPK3, P0DPK4, P35442, P46531, P78504, P97677, Q01705, Q04721, Q05793, Q07008, Q08E66, Q2QI47, Q5G872, Q5ZQU0, Q61483, Q63722, Q66PY1, Q6DI48, Q6NZL8, Q70E20, Q7TQN3, Q7Z3S9, Q8IWY4, Q8IX30, Q8JZM4, Q8K3K1, Q8NFT8, Q8TER0, Q8TEU8, Q8UWJ4, Q8VHS2, Q90Y54, Q90Y57

Diamond homologs: A0A096LNW5, A2RUV0, B4DH59, B8JI71, G3I6Z6, O35516, O75882, P07207, P0DPK3, P0DPK4, P10040, P21783, P46530, P46531, P98160, Q01705, Q04721, Q04756, Q07008, Q20911, Q7Z3S9, Q99466, Q99J86, Q9QW30, Q9UM47, Q9WU60, O35474, O75095, O89019, P13508, P20749, P31695, P82279, Q499M5, Q502K3, Q5RBP1, Q61982, Q6UXI9, Q6UY11, Q810B6

SIGNOR signaling

141 interactions.

A	Effect	B	Mechanism
POFUT1	up-regulates	NOTCH1	binding
SNW1	up-regulates	NOTCH1	binding
NOTCH1	“up-regulates quantity by expression”	NFKB1	“transcriptional regulation”
DLL4	“up-regulates activity”	NOTCH1	binding
NOTCH1	up-regulates	BMPR1A/1B/2
LCK	up-regulates	NOTCH1	binding
SMAD3	up-regulates	NOTCH1	binding
CNTN6	up-regulates	NOTCH1	relocalization
CCNC	down-regulates	NOTCH1	phosphorylation
CDK8	down-regulates	NOTCH1	phosphorylation
FBXW7	“down-regulates quantity by destabilization”	NOTCH1	ubiquitination
DNER	up-regulates	NOTCH1	binding
NOTCH1	“up-regulates activity”	HIF1A	relocalization
NOTCH1	“up-regulates quantity by expression”	ERBB2	“transcriptional regulation”
NOTCH1	“up-regulates quantity by expression”	FABP7	“transcriptional regulation”
HEY2	down-regulates	NOTCH1	binding
NOTCH1	“up-regulates quantity by expression”	MYC	“transcriptional regulation”
NOTCH1	“up-regulates quantity by expression”	BCL2	“transcriptional regulation”
NOTCH1	“up-regulates quantity by expression”	HOXA5	“transcriptional regulation”
NOTCH1	“up-regulates quantity by expression”	NOTCH1	“transcriptional regulation”
NOTCH1	“up-regulates quantity by expression”	TCFL5	“transcriptional regulation”
KAT5	down-regulates	NOTCH1	acetylation
HIF1AN	down-regulates	NOTCH1	hydroxylation
NLK	down-regulates	NOTCH1	phosphorylation
CCND1	up-regulates	NOTCH1
KPNA3	up-regulates	NOTCH1	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 143 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
Signaling by NOTCH2	7	52.6×	5e-09
Signaling by NOTCH3	8	43.7×	3e-09
Signaling by NOTCH4	8	41.8×	3e-09
Regulation of beta-cell development	5	37.6×	5e-06
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	5	37.6×	5e-06
NOTCH4 Intracellular Domain Regulates Transcription	6	36.1×	6e-07
Insulin receptor signalling cascade	5	35.4×	7e-06
Signaling by NOTCH1 PEST Domain Mutants in Cancer	8	34.4×	5e-09

GO biological processes:

GO term	Partners	Fold	FDR
thymus development	5	13.4×	4e-03
outflow tract morphogenesis	5	12.2×	5e-03
synapse organization	5	11.2×	6e-03
heart looping	5	10.6×	7e-03
positive regulation of cell differentiation	5	10.6×	7e-03
Notch signaling pathway	9	10.1×	1e-04
epidermal growth factor receptor signaling pathway	5	9.8×	9e-03
canonical Wnt signaling pathway	8	9.7×	5e-04

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

NOTCH1 is one of four known genes encoding the NOTCH family of proteins, a group of receptors involved in the Notch signaling pathway. NOTCH proteins are characterized by N-terminal EGF-like repeats followed by LNR domains which form a complex with ligands to prevent signaling. The Notch signaling pathway is involved in processes related to cell fate specification, differentiation, proliferation, and survival. Activation of Notch has been shown to be correlative with mammary tumorgenesis in mice and increased expression of Notch receptors has been observed in a variety of cancer types including cervical, colon, head and neck, lung, renal, pancreatic, leukemia, and breast cancer. A number of treatment modalities have been explored related to Notch inhibition especially in breast cancer with mixed results.

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 26 cancer types — ALL, ANGS, BCC, BLCA, BRCA, CESC, CHOL, CLLSLL, CSCC, DLBCLNOS, ESCA, HNSC…(+14 more).

Clinical variants and AI predictions

ClinVar

4454 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	92
Likely pathogenic	70
Uncertain significance	1530
Likely benign	1573
Benign	220

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072334	NM_017617.5(NOTCH1):c.4363C>T (p.Gln1455Ter)	Pathogenic
1074216	NM_017617.5(NOTCH1):c.4396C>T (p.Gln1466Ter)	Pathogenic
1075050	NM_017617.5(NOTCH1):c.1784_1787del (p.Tyr595fs)	Pathogenic
12476	NM_017617.5(NOTCH1):c.3319C>T (p.Arg1107Ter)	Pathogenic
12477	NM_017617.5(NOTCH1):c.4512del (p.Cys1505fs)	Pathogenic
1279937	NM_017617.5(NOTCH1):c.4668G>A (p.Trp1556Ter)	Pathogenic
1344732	NM_017617.5(NOTCH1):c.2272G>T (p.Glu758Ter)	Pathogenic
1344783	NM_017617.5(NOTCH1):c.3463C>T (p.Gln1155Ter)	Pathogenic
1344870	NM_017617.5(NOTCH1):c.2155G>T (p.Glu719Ter)	Pathogenic
1409179	NM_017617.5(NOTCH1):c.1800_1801dup (p.Glu601fs)	Pathogenic
1428655	NM_017617.5(NOTCH1):c.428del (p.Pro143fs)	Pathogenic
1453811	NM_017617.5(NOTCH1):c.763_773del (p.Glu255fs)	Pathogenic
1456559	NC_000009.11:g.(?139404165)(139405277_?)del	Pathogenic
1698389	NM_017617.5(NOTCH1):c.1116_1118delinsAC (p.Asn373fs)	Pathogenic
1723182	NM_017617.5(NOTCH1):c.6626_6629del (p.Tyr2209fs)	Pathogenic
1784431	NM_017617.5(NOTCH1):c.2012_2013dup (p.Gly672fs)	Pathogenic
1961662	NM_017617.5(NOTCH1):c.2759dup (p.Ser921fs)	Pathogenic
208337	NM_017617.5(NOTCH1):c.4775T>G (p.Phe1592Cys)	Pathogenic
2123517	NM_017617.5(NOTCH1):c.410C>A (p.Ser137Ter)	Pathogenic
2131756	NM_017617.5(NOTCH1):c.5310_5314dup (p.Gly1772fs)	Pathogenic
219375	NM_017617.5(NOTCH1):c.1343G>A (p.Arg448Gln)	Pathogenic
219378	NM_017617.5(NOTCH1):c.1649dup (p.Tyr550Ter)	Pathogenic
219380	NM_017617.5(NOTCH1):c.4663G>T (p.Glu1555Ter)	Pathogenic
219381	NM_017617.5(NOTCH1):c.4739dup (p.Met1580fs)	Pathogenic
221997	NM_017617.5(NOTCH1):c.3765C>A (p.Cys1255Ter)	Pathogenic
221998	NM_017617.5(NOTCH1):c.2439C>G (p.Tyr813Ter)	Pathogenic
221999	NM_017617.5(NOTCH1):c.578G>A (p.Gly193Asp)	Pathogenic
2631128	NM_017617.5(NOTCH1):c.2536C>T (p.Gln846Ter)	Pathogenic
2632882	NM_017617.5(NOTCH1):c.4315_4318dup (p.Ile1440fs)	Pathogenic
2633308	NM_017617.5(NOTCH1):c.2436del (p.Tyr813fs)	Pathogenic

SpliceAI

5610 predictions. Top by Δscore:

Variant	Effect	Δscore
9:136497557:TCC:T	acceptor_loss	1.0000
9:136497558:CCT:C	acceptor_loss	1.0000
9:136497560:T:A	acceptor_loss	1.0000
9:136498894:CTCA:C	donor_loss	1.0000
9:136498895:TCAC:T	donor_loss	1.0000
9:136498896:CACC:C	donor_loss	1.0000
9:136498897:A:AC	donor_gain	1.0000
9:136498897:AC:A	donor_gain	1.0000
9:136498898:C:CC	donor_gain	1.0000
9:136498898:C:CT	donor_loss	1.0000
9:136498898:CC:C	donor_gain	1.0000
9:136498915:T:C	donor_gain	1.0000
9:136498992:CTTGC:C	acceptor_gain	1.0000
9:136498993:TTGC:T	acceptor_gain	1.0000
9:136498994:TGC:T	acceptor_gain	1.0000
9:136498995:GC:G	acceptor_gain	1.0000
9:136498996:CC:C	acceptor_gain	1.0000
9:136498997:C:CC	acceptor_gain	1.0000
9:136498998:T:G	acceptor_loss	1.0000
9:136499000:C:CT	acceptor_gain	1.0000
9:136499001:G:C	acceptor_gain	1.0000
9:136499001:G:GC	acceptor_gain	1.0000
9:136499110:A:AC	donor_gain	1.0000
9:136499110:AC:A	donor_gain	1.0000
9:136499111:C:CC	donor_gain	1.0000
9:136499111:CC:C	donor_gain	1.0000
9:136499255:AGGAT:A	acceptor_gain	1.0000
9:136499258:AT:A	acceptor_gain	1.0000
9:136499259:TCTG:T	acceptor_loss	1.0000
9:136499260:C:CC	acceptor_gain	1.0000

AlphaMissense

16909 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:136499153:A:G	L2014P	1.000
9:136499255:A:G	L1980P	1.000
9:136500646:A:G	L1947P	1.000
9:136500655:G:T	A1944D	1.000
9:136500679:G:T	A1936D	1.000
9:136500685:A:G	L1934P	1.000
9:136511156:C:A	W861C	1.000
9:136511156:C:G	W861C	1.000
9:136517792:G:C	C467W	1.000
9:136517793:C:G	C467S	1.000
9:136517794:A:T	C467S	1.000
9:136517811:C:G	C461S	1.000
9:136517812:A:T	C461S	1.000
9:136517825:G:C	C456W	1.000
9:136517826:C:G	C456S	1.000
9:136517827:A:G	C456R	1.000
9:136517827:A:T	C456S	1.000
9:136517846:G:C	C449W	1.000
9:136517847:C:A	C449F	1.000
9:136517847:C:G	C449S	1.000
9:136517848:A:T	C449S	1.000
9:136517907:C:G	C429S	1.000
9:136517908:A:T	C429S	1.000
9:136518232:C:G	C387S	1.000
9:136518233:A:G	C387R	1.000
9:136518233:A:T	C387S	1.000
9:136518250:C:G	C381S	1.000
9:136518251:A:T	C381S	1.000
9:136518265:C:G	C376S	1.000
9:136518265:C:T	C376Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000052002 (9:136529557 G>A), RS1000087423 (9:136535485 C>T), RS1000141262 (9:136535334 G>A,C), RS1000208975 (9:136540656 T>C), RS1000260948 (9:136531596 C>G), RS1000318864 (9:136540337 T>C), RS1000329385 (9:136538191 G>A), RS1000443457 (9:136527517 C>A), RS1000470483 (9:136512967 G>A,C), RS1000503062 (9:136523623 C>A,G,T), RS1000654698 (9:136543762 C>T), RS1000674395 (9:136539036 T>C), RS1000715695 (9:136542852 ACCT>A), RS1000723986 (9:136531363 G>A), RS1000731251 (9:136519294 C>T)

Disease associations

OMIM: gene MIM:190198 | disease phenotypes: MIM:616028, MIM:607086, MIM:109730, MIM:100300, MIM:241550, MIM:154700, MIM:610805, MIM:187500, MIM:130020, MIM:162200, MIM:614219, MIM:118700, MIM:116200

GenCC curated gene-disease

Disease	Classification	Inheritance
Adams-Oliver syndrome	Definitive	Autosomal dominant
Adams-Oliver syndrome 5	Definitive	Autosomal dominant
genetic cerebral small vessel disease	Strong	Autosomal dominant
aortic valve disease 1	Strong	Autosomal dominant
leukodystrophy	Moderate	Autosomal dominant
connective tissue disorder	Moderate	Autosomal dominant
familial bicuspid aortic valve	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
NOTCH1-related AOS spectrum disorder	Definitive	AD

Mondo (26): Adams-Oliver syndrome 5 (MONDO:0014459), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625), aortic valve disease 1 (MONDO:0024523), cholesteatoma of middle ear (MONDO:0006533), myeloproliferative neoplasm, unclassifiable (MONDO:0019452), Adams-Oliver syndrome (MONDO:0007034), keratoacanthoma (MONDO:0002527), connective tissue disorder (MONDO:0003900), hypoplastic left heart syndrome (MONDO:0004933), pulmonary arterial hypertension (MONDO:0015924), Marfan syndrome (MONDO:0007947), early T cell progenitor acute lymphoblastic leukemia (MONDO:0100291), congenital heart disease (MONDO:0005453), congenital anomaly of kidney and urinary tract (MONDO:0019719), tetralogy of fallot (MONDO:0008542)

Orphanet (15): Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), Adams-Oliver syndrome (Orphanet:974), Chronic myeloproliferative disease, unclassifiable (Orphanet:86830), Hypoplastic left heart syndrome (Orphanet:2248), Pulmonary arterial hypertension (Orphanet:182090), Marfan syndrome type 1 (Orphanet:284963), Marfan syndrome (Orphanet:558), Renal or urinary tract malformation (Orphanet:93545), Microphthalmia-anophthalmia-coloboma (Orphanet:98555), Tetralogy of Fallot (Orphanet:3303), Hypermobile Ehlers-Danlos syndrome (Orphanet:285), Neurofibromatosis type 1 (Orphanet:636), Benign hereditary chorea (Orphanet:1429), Shone complex (Orphanet:99063), Idiopathic/heritable pulmonary arterial hypertension (Orphanet:422)

HPO phenotypes

79 total (30 of 79 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000238	Hydrocephalus
HP:0000486	Strabismus
HP:0000518	Cataract
HP:0000568	Microphthalmia
HP:0000822	Hypertension
HP:0000965	Cutis marmorata
HP:0001048	Cavernous hemangioma
HP:0001057	Aplasia cutis congenita
HP:0001156	Brachydactyly
HP:0001159	Syndactyly
HP:0001171	Split hand
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001269	Hemiparesis
HP:0001276	Hypertonia
HP:0001362	Calvarial skull defect
HP:0001394	Cirrhosis
HP:0001409	Portal hypertension
HP:0001508	Failure to thrive
HP:0001537	Umbilical hernia
HP:0001541	Ascites
HP:0001596	Alopecia
HP:0001622	Premature birth
HP:0001629	Ventricular septal defect
HP:0001636	Tetralogy of Fallot
HP:0001641	Abnormal pulmonary valve morphology
HP:0001642	Pulmonic stenosis
HP:0001647	Bicuspid aortic valve

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST003334_2	Length of menstrual cycle	2.000000e-08
GCST004131_21	Inflammatory bowel disease	5.000000e-36
GCST004132_11	Crohn’s disease	6.000000e-30
GCST004133_17	Ulcerative colitis	2.000000e-16
GCST005173_30	Coronary artery calcified atherosclerotic plaque (130 HU threshold) in type 2 diabetes	5.000000e-06
GCST005537_179	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	9.000000e-09
GCST006804_162	Red cell distribution width	6.000000e-09
GCST010244_103	Triglyceride levels	6.000000e-09
GCST90002381_306	Eosinophil count	2.000000e-21
GCST90002390_405	Mean corpuscular hemoglobin	7.000000e-09
GCST90011900_212	Serum alkaline phosphatase levels	4.000000e-19

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0009188	Red cell distribution width
EFO:0004530	triglyceride measurement
EFO:0004842	eosinophil count
EFO:0004527	mean corpuscular hemoglobin
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (14)

Descriptor	Name	Tree numbers
D017545	Aortic Aneurysm, Thoracic	C14.907.055.239.125; C14.907.109.139.125
D002386	Cataract	C11.510.245
D018424	Cholesteatoma, Middle Ear	C09.218.200; C17.800.428.260.300
D003240	Connective Tissue Diseases	C17.300
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D018636	Hypoplastic Left Heart Syndrome	C14.240.400.625; C14.280.400.625; C16.131.240.400.625
D007636	Keratoacanthoma	C17.800.417
D008382	Marfan Syndrome	C05.116.099.674; C14.240.400.725; C14.280.400.725; C16.131.077.550; C16.131.240.400.720; C16.320.540; C17.300.500
D009456	Neurofibromatosis 1	C04.557.580.600.580.590.650; C04.700.631.650; C10.562.600.500; C10.574.500.549.400; C10.668.829.675; C16.320.400.560.400; C16.320.700.633.650
D000081029	Pulmonary Arterial Hypertension	C08.381.423.847
D013771	Tetralogy of Fallot	C14.240.400.849; C14.280.400.849; C16.131.240.400.849
C538225	Adams Oliver syndrome (supp.)
C566906	Cakut (supp.)
C536196	Ehlers-Danlos syndrome type 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2146346 (SINGLE PROTEIN), CHEMBL4524007 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 54 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3911164	VAREGACESTAT	2	54

Clinical evidence (CIViC)

Drug × variant × indication: 3 predictive associations from 4 curated evidence items; also 12 prognostic, 2 oncogenic.

Variant	Therapy	Indication	Effect	Level	CIViC
NOTCH1 Mutation	Prednisone	T-cell Acute Lymphoblastic Leukemia	Sensitivity/Response	CIViC C	EID2692 +1
NOTCH1 Amplification	NOTCH1 Antibody (PF-06293622)	Colorectal Cancer	Sensitivity/Response	CIViC D	EID811
NOTCH1 Loss-of-function	Porcupine Inhibitor WNT974	Head And Neck Squamous Cell Carcinoma	Sensitivity/Response	CIViC D	EID1525

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — Notch receptors

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
brontictuzumab	Binding	8.36	pKd
IMR-1	Binding	4.96	pKd

Binding affinities (BindingDB)

64 measured of 65 human assays (65 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S,3R)-N’-[(3S)-9-cyclopropyl-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	1.4 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-9-methyl-2-oxo-5-[3-(trifluoromethyl)phenyl]-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	1.6 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-9-chloro-5-(3-cyclopropylphenyl)-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	1.7 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-9-chloro-5-(3-methylphenyl)-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-[(3,3-difluorocyclobutyl)methyl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	1.7 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-N’-[(3S)-5-(3-chlorophenyl)-2-oxo-9-propan-2-yl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	1.8 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-2-[(3,3-difluorocyclobutyl)methyl]-N’-[(3S)-9-fluoro-5-(3-methylphenyl)-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	2.1 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-N’-[(3S)-9-chloro-5-(3,5-dimethylphenyl)-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(4,4,4-trifluorobutyl)-3-(3,3,3-trifluoropropyl)butanediamide	IC50	2.3 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-9-chloro-5-(3,5-dimethylphenyl)-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	2.5 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-2-(2,2-difluoropropyl)-N’-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	2.7 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-N’-[(3S)-5-(4-chlorophenyl)-9-methoxy-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	2.8 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-5-(2-methylphenyl)-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	2.8 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-9-chloro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-[(3,3-difluorocyclobutyl)methyl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	2.8 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-2-[(3,3-difluorocyclobutyl)methyl]-N’-[(3S)-9-methoxy-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	2.9 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-N’-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-[(2S)-3,3,3-trifluoro-2-methylpropyl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	2.9 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-N’-[(3S)-5-(3-methylphenyl)-2-oxo-9-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	3 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-5-(3-methylphenyl)-2-oxo-9-propan-2-yl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	3 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-2-[(3,3-difluorocyclobutyl)methyl]-N’-[(3S)-9-methyl-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	3 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-N’-[(3S)-5-(4-fluorophenyl)-9-methyl-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	3.1 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-9-chloro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-[(2R)-3,3,3-trifluoro-2-methylpropyl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	3.2 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-N’-[(3S)-9-chloro-5-(2-methylphenyl)-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	3.3 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-2-oxo-5-phenyl-9-propan-2-yl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	3.4 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-2-[(3,3-difluorocyclobutyl)methyl]-N’-[(3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	3.5 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-N’-[(3S)-5-(3-chlorophenyl)-9-methoxy-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	3.7 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-2-[(1-fluorocyclobutyl)methyl]-N’-[(3S)-9-methyl-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	3.8 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-N’-[(3S)-9-methoxy-5-(3-methylphenyl)-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	3.9 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-9-cyclopropyloxy-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-[(3,3-difluorocyclobutyl)methyl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	3.9 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-N’-[(3S)-9-chloro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(3,3-difluorobutyl)-3-(3,3,3-trifluoropropyl)butanediamide	IC50	3.9 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-N’-[(3S)-9-cyclopropyloxy-5-(3-fluorophenyl)-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(4,4-difluorocyclohexyl)-3-(3,3,3-trifluoropropyl)butanediamide	IC50	4.2 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-N’-[(3S)-5-[4-(hydroxymethyl)phenyl]-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	4.3 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-9-methoxy-2-oxo-5-[5-(trifluoromethyl)-2-pyridinyl]-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	4.3 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-5-(3-chlorophenyl)-9-methyl-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	4.4 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-9-cyclopropyloxy-5-(3-methylphenyl)-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	4.4 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-9-chloro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(4,4-difluorocyclohexyl)-3-(3,3,3-trifluoropropyl)butanediamide	IC50	4.4 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-2-[(3,3-difluorocyclobutyl)methyl]-N’-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	4.4 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-2-[(3,3-difluorocyclobutyl)methyl]-N’-[(3S)-9-fluoro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	4.5 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-N’-[(3S)-9-methyl-2-oxo-5-[3-(trifluoromethyl)phenyl]-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(4,4,4-trifluorobutyl)-3-(3,3,3-trifluoropropyl)butanediamide	IC50	4.6 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-9-methyl-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	4.7 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-9-cyclopropyloxy-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	4.8 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-9-chloro-5-(3-methylphenyl)-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	4.8 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-5-(5-chloro-2-pyridinyl)-9-methoxy-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	4.8 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-5-(3-chlorophenyl)-9-ethyl-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	4.9 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-2-butyl-N’-[(3S)-5-(4-chlorophenyl)-1-methyl-2-oxo-3H-1,4-benzodiazepin-3-yl]-3-(2-methylpropyl)butanediamide	IC50	5.1 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-9-chloro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-[(2S)-3,3,3-trifluoro-2-methylpropyl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	5.1 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-N’-[(3S)-9-cyclopropyl-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-[(3,3-difluorocyclobutyl)methyl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	5.6 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-N’-[(3S)-9-chloro-5-(3-methylphenyl)-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(4,4,4-trifluorobutyl)-3-(3,3,3-trifluoropropyl)butanediamide	IC50	5.7 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-9-cyclopropyloxy-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(4,4,4-trifluorobutyl)-3-(3,3,3-trifluoropropyl)butanediamide	IC50	5.8 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-2-(3-fluoropropyl)-N’-[(3S)-8-methoxy-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	5.8 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-N’-[(3S)-5-(3-chlorophenyl)-9-methyl-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(4,4,4-trifluorobutyl)-3-(3,3,3-trifluoropropyl)butanediamide	IC50	6 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-5-(3-fluorophenyl)-9-(hydroxymethyl)-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	6.2 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-5-(3-methylphenyl)-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)butanediamide	IC50	6.4 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof

ChEMBL bioactivities

114 potent at pChembl≥5 of 118 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL3410169
9.00	IC50	1	nM	CHEMBL3410163
9.00	IC50	1	nM	CHEMBL3410153
8.85	IC50	1.4	nM	CHEMBL3922868
8.80	IC50	1.6	nM	CHEMBL3908473
8.77	IC50	1.7	nM	CHEMBL3929363
8.77	IC50	1.7	nM	CHEMBL4109925
8.74	IC50	1.8	nM	CHEMBL3896661
8.70	IC50	2	nM	CHEMBL3410170
8.70	IC50	2	nM	CHEMBL3410168
8.70	IC50	2	nM	CHEMBL3410167
8.70	IC50	2	nM	CHEMBL3410151
8.70	IC50	2	nM	CHEMBL4644426
8.68	IC50	2.1	nM	CHEMBL4114579
8.64	IC50	2.3	nM	CHEMBL3915833
8.60	IC50	2.5	nM	CHEMBL3944645
8.57	IC50	2.7	nM	CHEMBL4111709
8.55	IC50	2.8	nM	CHEMBL3973748
8.55	IC50	2.8	nM	CHEMBL3984170
8.55	IC50	2.8	nM	CHEMBL4114126
8.54	IC50	2.9	nM	CHEMBL4112577
8.54	IC50	2.9	nM	CHEMBL3921166
8.52	IC50	3	nM	CHEMBL3410164
8.52	IC50	3	nM	CHEMBL3410162
8.52	IC50	3	nM	CHEMBL3410160
8.52	IC50	3	nM	CHEMBL3410152
8.52	IC50	3	nM	CHEMBL3913200
8.52	IC50	3	nM	CHEMBL3984723
8.52	IC50	3	nM	CHEMBL4111904
8.52	IC50	3	nM	CHEMBL4645821
8.51	IC50	3.1	nM	CHEMBL3938447
8.49	IC50	3.2	nM	CHEMBL4108896
8.48	IC50	3.3	nM	CHEMBL3919904
8.47	IC50	3.4	nM	CHEMBL3983707
8.46	IC50	3.5	nM	CHEMBL4107767
8.43	IC50	3.7	nM	CHEMBL3935299
8.42	IC50	3.8	nM	CHEMBL4107530
8.41	IC50	3.9	nM	CHEMBL3895390
8.41	IC50	3.9	nM	CHEMBL4112855
8.41	IC50	3.9	nM	CHEMBL3935675
8.40	IC50	4	nM	CHEMBL3410161
8.38	IC50	4.2	nM	CHEMBL4108092
8.37	IC50	4.3	nM	CHEMBL3960841
8.37	IC50	4.3	nM	CHEMBL3909875
8.36	IC50	4.4	nM	CHEMBL3891599
8.36	IC50	4.4	nM	CHEMBL3923405
8.36	IC50	4.4	nM	CHEMBL4112450
8.36	IC50	4.4	nM	CHEMBL4107070
8.35	IC50	4.5	nM	CHEMBL4111071
8.34	IC50	4.6	nM	CHEMBL3965388

PubChem BioAssay actives

44 with measured affinity, of 91 total; 44 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
(2S,3R)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-2-pentan-3-yl-3-(3,3,3-trifluoropropyl)butanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0010	uM
(2R,3R)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-2-[3-(trifluoromethyl)phenyl]-3-(3,3,3-trifluoropropyl)butanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0010	uM
(2R,3R)-2-(2,4-difluorophenyl)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0010	uM
(2R,3R)-2-(3,4-difluorophenyl)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0020	uM
(2R,3R)-2-(3,5-difluorophenyl)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0020	uM
(9S)-N-[(1S,5R)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine	1658578: Inhibition of human Notch1 expressed in HEK293 cells coexpressing luciferase reporter measured after 20 hrs by chemiluminescence assay	ic50	0.0020	uM
(2S,3R)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-3-(2-methylpropyl)-2-pentan-3-ylbutanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0020	uM
(2R,3R)-2-(4-fluorophenyl)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0020	uM
(2S,3R)-3-(2,2-dimethylpropyl)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-2-pentan-3-ylbutanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0030	uM
(2R,3R)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-2-(3-methylphenyl)-3-(3,3,3-trifluoropropyl)butanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0030	uM
(2R,3R)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-2-[3-(trifluoromethoxy)phenyl]-3-(3,3,3-trifluoropropyl)butanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0030	uM
4-(3,5-difluorophenyl)-N-[(1R,5S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine	1658578: Inhibition of human Notch1 expressed in HEK293 cells coexpressing luciferase reporter measured after 20 hrs by chemiluminescence assay	ic50	0.0030	uM
(2R,3R)-2-(3-methyl-1,2-oxazol-4-yl)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0030	uM
(2R,3R)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-2-phenyl-3-(3,3,3-trifluoropropyl)butanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0040	uM
(2R,3R)-2-(4-methoxyphenyl)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0090	uM
(2S,3R)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-2-propyl-3-(2,2,2-trifluoroethyl)butanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0130	uM
(2R,3R)-2-(1,2-oxazol-4-yl)-N’-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0320	uM
(2R,3R)-2-(5-methyl-1,2-oxazol-3-yl)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0540	uM
[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]methyl (4R)-4-(3-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,6,8-tetrahydroquinoline-3-carboxylate	1420878: Inhibition of Notch1 deltaE mutant (unknown origin) expressed in HEK293 cells after 16 hrs by resazurin dye-based luciferase reporter gene assay	ic50	0.1300	uM
(2R,3R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.1690	uM
[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]methyl 4-(3-cyanophenyl)-2,7,7-trimethyl-5-oxo-1,4,6,8-tetrahydroquinoline-3-carboxylate	1420878: Inhibition of Notch1 deltaE mutant (unknown origin) expressed in HEK293 cells after 16 hrs by resazurin dye-based luciferase reporter gene assay	ic50	0.2200	uM
(2R,3R)-2-(1,3-oxazol-4-yl)-N’-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.2310	uM
(1’S,2S,3’R,5’S,7’R,10’R,12’R,14’R,15’S,18’R,19’R,22’S,23’R)-10’,22’-dihydroxy-7’,18’-dimethyl-4-oxo-19’-(5-oxo-2H-furan-3-yl)spiro[1,3-thiazolidine-2,9’-4,6,11-trioxahexacyclo[12.11.0.03,12.05,10.015,23.018,22]pentacosane]-14’-carbaldehyde	1500975: Inhibition of recombinant mouse N-terminal FLAG-tagged Notch1 (1704 to 2531 residues) expressed in human LS174T cells assessed as reduction in doxycycline-induced NICD expression after 12 hrs by Bright-Glo luciferase reporter gene assay	ic50	0.3000	uM
[(1S,3R,5S,7R,9S,10S,12R,14R,15S,18R,19R,22S,23R)-14-formyl-10,22-dihydroxy-7,18-dimethyl-19-(5-oxo-2H-furan-3-yl)-4,6,11-trioxahexacyclo[12.11.0.03,12.05,10.015,23.018,22]pentacosan-9-yl] acetate	1500975: Inhibition of recombinant mouse N-terminal FLAG-tagged Notch1 (1704 to 2531 residues) expressed in human LS174T cells assessed as reduction in doxycycline-induced NICD expression after 12 hrs by Bright-Glo luciferase reporter gene assay	ic50	0.3000	uM
[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]methyl 2,7,7-trimethyl-5-oxo-4-quinolin-2-yl-1,4,6,8-tetrahydroquinoline-3-carboxylate	1420878: Inhibition of Notch1 deltaE mutant (unknown origin) expressed in HEK293 cells after 16 hrs by resazurin dye-based luciferase reporter gene assay	ic50	0.3300	uM
[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]methyl 4-(3-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,6,8-tetrahydroquinoline-3-carboxylate	1420878: Inhibition of Notch1 deltaE mutant (unknown origin) expressed in HEK293 cells after 16 hrs by resazurin dye-based luciferase reporter gene assay	ic50	0.3600	uM
(1S,3R,5S,7R,9S,10R,12R,14R,15S,18R,19R,22S,23R)-10,22-dihydroxy-7,18-dimethyl-19-(5-oxo-2H-furan-3-yl)spiro[4,6,11-trioxahexacyclo[12.11.0.03,12.05,10.015,23.018,22]pentacosane-9,2’-5H-1,3-thiazole]-14-carbaldehyde	1500975: Inhibition of recombinant mouse N-terminal FLAG-tagged Notch1 (1704 to 2531 residues) expressed in human LS174T cells assessed as reduction in doxycycline-induced NICD expression after 12 hrs by Bright-Glo luciferase reporter gene assay	ic50	0.4000	uM
[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]methyl 4-(3,5-dichlorophenyl)-2,7,7-trimethyl-5-oxo-1,4,6,8-tetrahydroquinoline-3-carboxylate	1420878: Inhibition of Notch1 deltaE mutant (unknown origin) expressed in HEK293 cells after 16 hrs by resazurin dye-based luciferase reporter gene assay	ic50	0.6400	uM
(1S,3R,5S,7R,9S,10R,12R,14R,15S,18R,19R,20R,22S,23R)-10,20,22-trihydroxy-7,18-dimethyl-19-(5-oxo-2H-furan-3-yl)spiro[4,6,11-trioxahexacyclo[12.11.0.03,12.05,10.015,23.018,22]pentacosane-9,2’-5H-1,3-thiazole]-14-carbaldehyde	1500975: Inhibition of recombinant mouse N-terminal FLAG-tagged Notch1 (1704 to 2531 residues) expressed in human LS174T cells assessed as reduction in doxycycline-induced NICD expression after 12 hrs by Bright-Glo luciferase reporter gene assay	ic50	0.7000	uM
[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]methyl 2,7,7-trimethyl-5-oxo-4-[3-(trifluoromethyl)phenyl]-1,4,6,8-tetrahydroquinoline-3-carboxylate	1420878: Inhibition of Notch1 deltaE mutant (unknown origin) expressed in HEK293 cells after 16 hrs by resazurin dye-based luciferase reporter gene assay	ic50	0.7600	uM
[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]methyl 4-[3-(1H-indol-5-yl)phenyl]-2,7,7-trimethyl-5-oxo-1,4,6,8-tetrahydroquinoline-3-carboxylate	1420878: Inhibition of Notch1 deltaE mutant (unknown origin) expressed in HEK293 cells after 16 hrs by resazurin dye-based luciferase reporter gene assay	ic50	0.7700	uM
(1S,3R,5S,7R,9S,10S,12R,14R,15S,18R,19R,22S,23R)-9,10,22-trihydroxy-7,18-dimethyl-19-(5-oxo-2H-furan-3-yl)-4,6,11-trioxahexacyclo[12.11.0.03,12.05,10.015,23.018,22]pentacosane-14-carbaldehyde	1500975: Inhibition of recombinant mouse N-terminal FLAG-tagged Notch1 (1704 to 2531 residues) expressed in human LS174T cells assessed as reduction in doxycycline-induced NICD expression after 12 hrs by Bright-Glo luciferase reporter gene assay	ic50	0.8000	uM
pyrazin-2-ylmethyl 4-(3-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,6,8-tetrahydroquinoline-3-carboxylate	1420878: Inhibition of Notch1 deltaE mutant (unknown origin) expressed in HEK293 cells after 16 hrs by resazurin dye-based luciferase reporter gene assay	ic50	0.8600	uM
(2R,3R)-2-(1,2,4-oxadiazol-3-yl)-N’-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	1.1900	uM
[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]methyl 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-2,7,7-trimethyl-5-oxo-1,4,6,8-tetrahydroquinoline-3-carboxylate	1420878: Inhibition of Notch1 deltaE mutant (unknown origin) expressed in HEK293 cells after 16 hrs by resazurin dye-based luciferase reporter gene assay	ic50	1.5200	uM
(1’S,2S,3’R,5’S,7’R,10’R,12’R,14’R,15’S,18’R,19’R,22’S,23’R)-10’,22’-dihydroxy-7’,18’-dimethyl-19’-(5-oxo-2H-furan-3-yl)spiro[1,3-thiazolidine-2,9’-4,6,11-trioxahexacyclo[12.11.0.03,12.05,10.015,23.018,22]pentacosane]-14’-carbaldehyde	1500975: Inhibition of recombinant mouse N-terminal FLAG-tagged Notch1 (1704 to 2531 residues) expressed in human LS174T cells assessed as reduction in doxycycline-induced NICD expression after 12 hrs by Bright-Glo luciferase reporter gene assay	ic50	2.0000	uM
(2R,3R)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-2-(3-methylsulfonylphenyl)-3-(3,3,3-trifluoropropyl)butanediamide	1198933: Inhibition of Notch1 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	2.0600	uM
(1S,3R,5S,7R,10R,12R,14R,15S,18R,19R,22S,23R)-10,22-dihydroxy-7,18-dimethyl-9-oxo-19-(5-oxo-2H-furan-3-yl)-4,6,11-trioxahexacyclo[12.11.0.03,12.05,10.015,23.018,22]pentacosane-14-carbaldehyde	1500975: Inhibition of recombinant mouse N-terminal FLAG-tagged Notch1 (1704 to 2531 residues) expressed in human LS174T cells assessed as reduction in doxycycline-induced NICD expression after 12 hrs by Bright-Glo luciferase reporter gene assay	ic50	2.4000	uM
cyclohexyl 2,7,7-trimethyl-4-(4-nitrophenyl)-5-oxo-1,4,6,8-tetrahydroquinoline-3-carboxylate	1420878: Inhibition of Notch1 deltaE mutant (unknown origin) expressed in HEK293 cells after 16 hrs by resazurin dye-based luciferase reporter gene assay	ic50	2.5100	uM
[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]methyl (4S)-4-(3-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,6,8-tetrahydroquinoline-3-carboxylate	1420878: Inhibition of Notch1 deltaE mutant (unknown origin) expressed in HEK293 cells after 16 hrs by resazurin dye-based luciferase reporter gene assay	ic50	2.5900	uM
2-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]ethyl 4-(3-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,6,8-tetrahydroquinoline-3-carboxylate	1420878: Inhibition of Notch1 deltaE mutant (unknown origin) expressed in HEK293 cells after 16 hrs by resazurin dye-based luciferase reporter gene assay	ic50	2.9500	uM
[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]methyl 2,7,7-trimethyl-5-oxo-4-(3-propan-2-ylphenyl)-1,4,6,8-tetrahydroquinoline-3-carboxylate	1420878: Inhibition of Notch1 deltaE mutant (unknown origin) expressed in HEK293 cells after 16 hrs by resazurin dye-based luciferase reporter gene assay	ic50	3.3200	uM
cyclohexyl 4-(3-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,6,8-tetrahydroquinoline-3-carboxylate	1420878: Inhibition of Notch1 deltaE mutant (unknown origin) expressed in HEK293 cells after 16 hrs by resazurin dye-based luciferase reporter gene assay	ic50	4.1500	uM
(4-tert-butylphenyl)methyl 4-(3-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,6,8-tetrahydroquinoline-3-carboxylate	1420878: Inhibition of Notch1 deltaE mutant (unknown origin) expressed in HEK293 cells after 16 hrs by resazurin dye-based luciferase reporter gene assay	ic50	4.2700	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	decreases expression, increases expression, increases activity, decreases response to substance, decreases reaction (+3 more)	11
sodium arsenite	affects expression, decreases reaction, increases activity, decreases expression, increases expression	6
N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester	increases expression, increases cleavage, increases activity, increases reaction, decreases activity (+3 more)	6
Resveratrol	increases expression, affects expression, decreases expression, decreases reaction, increases activity	5
Tretinoin	affects cotreatment, increases expression, decreases expression	5
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases expression, decreases reaction, increases degradation, increases expression	4
MRK 003	decreases reaction, increases activity, decreases cleavage, decreases phosphorylation	4
Valproic Acid	decreases expression, decreases reaction, increases methylation	4
bisphenol A	affects cotreatment, increases methylation, decreases expression	3
arsenite	affects binding, decreases reaction, decreases expression, increases expression	3
(+)-JQ1 compound	increases response to substance, decreases expression, increases expression	3
Estradiol	affects cotreatment, decreases expression, affects binding, increases reaction, increases expression	3
Quercetin	decreases expression, decreases reaction, increases cleavage, affects cleavage, affects cotreatment (+1 more)	3
Tobacco Smoke Pollution	decreases expression	3
Cadmium Chloride	affects reaction, increases phosphorylation, increases hydroxylation, increases abundance, increases expression (+4 more)	3
Particulate Matter	affects reaction, decreases expression, increases cleavage, increases abundance, increases expression (+1 more)	3
N-((3,5-difluorophenyl)acetyl)alanyl-2-phenylglycine-1,1-dimethylethyl ester	decreases reaction, increases cleavage, decreases expression	2
trichostatin A	affects cotreatment, decreases expression, decreases reaction, increases expression	2
mono-(2-ethylhexyl)phthalate	increases abundance, increases expression, increases methylation	2
RTKI cpd	decreases expression, decreases reaction, increases cleavage, increases expression	2
U 0126	decreases reaction, increases activity	2
Decitabine	increases expression, affects cotreatment, decreases expression, decreases reaction	2
Acetaminophen	increases expression	2
Glyphosate	increases expression, increases activity	2
Air Pollutants	increases expression, decreases reaction, affects expression, increases abundance	2
Cadmium	increases abundance, increases expression	2
Cisplatin	decreases expression, increases expression, affects reaction, increases cleavage, increases reaction	2
Curcumin	affects cotreatment, decreases expression	2
Diethylhexyl Phthalate	increases expression, increases methylation, increases abundance	2
Smoke	decreases expression	2

ChEMBL screening assays

23 unique, capped per target: 19 binding, 4 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2150378	Binding	Inhibition of NICD-mediated HES1 protein expression in human H4 cells at 10 uM after 24 hrs by Western blot analysis	Discovery of BIIB042, a Potent, Selective, and Orally Bioavailable γ-Secretase Modulator. — ACS Med Chem Lett
CHEMBL3398717	ADMET	Inhibition of NOTCH-1 signaling (unknown origin) expressed in CHO cells at 5 to 50 uM after 24 hrs by dual luciferase reporter gene assay	SAR-studies of γ-secretase modulators with PPARγ-agonistic and 5-lipoxygenase-inhibitory activity for Alzheimer’s disease. — Bioorg Med Chem Lett

Cellosaurus cell lines

244 cell lines: 227 cancer cell line, 7 induced pluripotent stem cell, 6 telomerase immortalized cell line, 2 spontaneously immortalized cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0013	MOLT-4	Cancer cell line	Male
CVCL_0065	Jurkat	Cancer cell line	Male
CVCL_0138	ACH-2	Cancer cell line	Female
CVCL_0207	CCRF-CEM	Cancer cell line	Female
CVCL_0624	MOLT-3	Cancer cell line	Male
CVCL_0C87	MOCHA	Cancer cell line	Male
CVCL_0R18	CEM-TART clone 1A2	Cancer cell line	Female
CVCL_0U11	CEM/MX1	Cancer cell line	Female
CVCL_1081	BE-13	Cancer cell line	Female
CVCL_1090	BONNA-12	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04197050	PHASE4	UNKNOWN	Effect of Sacubitril/Valsartan on Reduced Right Ventricular Ejection Fraction in Patients With CTD
NCT04928586	PHASE4	UNKNOWN	Immunosuppressant Combined With Pirfenidone in CTD-ILD
NCT05440240	PHASE4	RECRUITING	Percutaneous Needle Fasciotomy +/- Corticosteroid Injection for Dupuytren’s Contracture
NCT05505409	PHASE4	UNKNOWN	Efficacy and Safety of Pirfenidone in CTD-ILD
NCT06499233	PHASE4	RECRUITING	Efficacy and Safety of Prophylactic Treatment for Pneumocystis Jirovecii Pneumonia in Patients With Autoimmune Inflammatory Rheumatic Disease
NCT03630198	PHASE4	COMPLETED	Pain Outcomes Following Intralesional Corticosteroid Injections
NCT00864201	PHASE3	UNKNOWN	A Study to Evaluate the Use of Bosentan in Patients With Exercise Induced Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
NCT01196091	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01205438	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01488708	PHASE3	TERMINATED	On Open-Label Study in Participants With Systemic Lupus Erythematosus
NCT03626688	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
NCT03683186	PHASE3	ENROLLING_BY_INVITATION	A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
NCT04084678	PHASE3	TERMINATED	A Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH
NCT06716606	PHASE3	RECRUITING	A Study to Investigate the Long-term Safety and Efficacy of Belimumab in Adults With Interstitial Lung Disease (ILD) Associated With Systemic Sclerosis (SSc) and Other Connective Tissue Diseases (CTD) (BLISSconneCTD-OLE)
NCT06917690	PHASE3	RECRUITING	A Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa
NCT00322101	PHASE3	COMPLETED	Low-Dose or High-Dose Conditioning Followed by Peripheral Blood Stem Cell Transplant in Treating Patients With Myelodysplastic Syndrome or Acute Myelogenous Leukemia
NCT00799461	PHASE3	COMPLETED	Internet-Based Program With or Without Telephone-Based Problem-Solving Training in Helping Long-Term Survivors of Hematopoietic Stem Cell Transplant Cope With Late Complications
NCT01305200	PHASE3	COMPLETED	Supersaturated Calcium Phosphate Rinse in Preventing Oral Mucositis in Young Patients Undergoing Autologous or Donor Stem Cell Transplant
NCT02781922	PHASE3	RECRUITING	Cardiac Stem/Progenitor Cell Infusion in Univentricular Physiology (APOLLON Trial)
NCT00004357	PHASE2	COMPLETED	Absorption of Corticosteroids in Children With Juvenile Dermatomyositis
NCT00005675	PHASE2	COMPLETED	Oral Type I Collagen for Relieving Scleroderma
NCT01808196	PHASE2	COMPLETED	Testing Effectiveness of Losartan in Patients With EoE With or Without a CTD
NCT02682511	PHASE2	ACTIVE_NOT_RECRUITING	Oral Ifetroban to Treat Diffuse Cutaneous Systemic Sclerosis (SSc) or SSc-associated Pulmonary Arterial Hypertension
NCT04993885	PHASE2	RECRUITING	Avatrombopag in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT05516758	PHASE2	TERMINATED	A Study of Peresolimab (LY3462817) in Participants With Moderately-to-Severely Active Rheumatoid Arthritis
NCT05998759	PHASE2	RECRUITING	Telitacicept for the Treatment of Connective Tissue Disease-associated Thrombocytopenia
NCT06104228	PHASE2	RECRUITING	129 Xenon MRI as a Biomarker for Diagnosis and Response to Therapy in Pulmonary Arterial Hypertension (PAH)
NCT00040846	PHASE2	COMPLETED	Alemtuzumab, Fludarabine Phosphate, and Low-Dose Total Body Irradiation Before Donor Stem Cell Transplantation in Treating Patients With Hematological Malignancies
NCT00105001	PHASE2	COMPLETED	Tacrolimus and Mycophenolate Mofetil With or Without Sirolimus in Preventing Acute Graft-Versus-Host Disease in Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer
NCT00118352	PHASE2	COMPLETED	Alemtuzumab, Fludarabine Phosphate, and Total-Body Irradiation Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer
NCT00462605	PHASE2	COMPLETED	MS-275 and GM-CSF in Treating Patients With Myelodysplastic Syndrome and/or Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphocytic Leukemia
NCT00509249	PHASE2	TERMINATED	Aflibercept in Treating Patients With Myelodysplastic Syndromes
NCT00530218	PHASE2	COMPLETED	Ganciclovir by Infusion and by Mouth in Treating Patients With Cytomegalovirus After Donor Bone Marrow Transplant
NCT00795769	PHASE2	COMPLETED	Ondansetron in Preventing Nausea and Vomiting in Patients Undergoing Stem Cell Transplant
NCT01056614	PHASE2	COMPLETED	Fludarabine Phosphate, Busulfan, and Anti-Thymocyte Globulin Followed By Donor Peripheral Blood Stem Cell Transplant, Tacrolimus, and Methotrexate in Treating Patients With Myeloid Malignancies
NCT01093586	PHASE2	COMPLETED	Donor Umbilical Cord Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT01159067	PHASE2	TERMINATED	Deferasirox for Treating Patients Who Have Undergone Allogeneic Stem Cell Transplant and Have Iron Overload