NOTCH3

Summary

NOTCH3 (notch receptor 3, HGNC:7883) is a protein-coding gene on chromosome 19p13.12, encoding Neurogenic locus notch homolog protein 3 (Q9UM47). Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination.

This gene encodes the third discovered human homologue of the Drosophilia melanogaster type I membrane protein notch. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined. Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Source: NCBI Gene 4854 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (Definitive, GenCC) — +5 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 2,051 total — 169 pathogenic, 91 likely-pathogenic
• Phenotypes (HPO): 295
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000435

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7883
Approved symbol	NOTCH3
Name	notch receptor 3
Location	19p13.12
Locus type	gene with protein product
Status	Approved
Aliases	CASIL
Ensembl gene	ENSG00000074181
Ensembl biotype	protein_coding
OMIM	600276
Entrez	4854

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000263388, ENST00000595045, ENST00000595514, ENST00000597756, ENST00000600841, ENST00000601011, ENST00000931532, ENST00000931533, ENST00000931534, ENST00000931535

RefSeq mRNA: 1 — MANE Select: NM_000435 NM_000435

CCDS: CCDS12326

Canonical transcript exons

ENST00000263388 — 33 exons

Exon	Start	End
ENSE00000348718	15191424	15191657
ENSE00000348722	15187881	15187994
ENSE00000348725	15185487	15185679
ENSE00000689088	15192377	15192519
ENSE00000689090	15191960	15192298
ENSE00000689218	15191745	15191867
ENSE00000689251	15189273	15189428
ENSE00000689254	15188989	15189174
ENSE00000689256	15188235	15188348
ENSE00000689261	15187105	15187338
ENSE00000689390	15186878	15186988
ENSE00000689392	15185257	15185408
ENSE00000689413	15184906	15185019
ENSE00000689414	15184295	15184450
ENSE00000689441	15181576	15181801
ENSE00000689475	15180961	15181162
ENSE00000689476	15180681	15180828
ENSE00000689477	15180072	15180256
ENSE00000689480	15178823	15178941
ENSE00000689482	15174068	15174400
ENSE00000689484	15170671	15170825
ENSE00000689485	15170331	15170553
ENSE00000689486	15170086	15170170
ENSE00000689488	15167249	15167411
ENSE00000689489	15165787	15166091
ENSE00000873265	15159038	15161714
ENSE00000873267	15179364	15179496
ENSE00000873268	15200788	15200995
ENSE00001113195	15197500	15197578
ENSE00002724304	15177525	15178090
ENSE00003576639	15162465	15162562
ENSE00003591200	15165368	15165515
ENSE00003688412	15179025	15179282

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 98.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.9333 / max 420.9005, expressed in 1344 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
179709	26.0982	1341
179710	0.8351	320

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
popliteal artery	UBERON:0002250	98.66	gold quality
tibial artery	UBERON:0007610	98.66	gold quality
right coronary artery	UBERON:0001625	98.58	gold quality
artery	UBERON:0001637	98.40	gold quality
aorta	UBERON:0000947	98.04	gold quality
ventricular zone	UBERON:0003053	98.02	gold quality
descending thoracic aorta	UBERON:0002345	97.41	gold quality
endometrium epithelium	UBERON:0004811	97.40	gold quality
blood vessel layer	UBERON:0004797	97.39	gold quality
thoracic aorta	UBERON:0001515	97.27	gold quality
ascending aorta	UBERON:0001496	97.23	gold quality
coronary artery	UBERON:0001621	97.22	gold quality
left coronary artery	UBERON:0001626	97.20	gold quality
saphenous vein	UBERON:0007318	96.73	gold quality
skin of leg	UBERON:0001511	96.72	gold quality
stromal cell of endometrium	CL:0002255	96.71	gold quality
apex of heart	UBERON:0002098	96.57	gold quality
pericardium	UBERON:0002407	96.51	gold quality
skin of abdomen	UBERON:0001416	96.23	gold quality
tendon of biceps brachii	UBERON:0008188	95.83	gold quality
vagina	UBERON:0000996	95.60	gold quality
zone of skin	UBERON:0000014	95.36	gold quality
subcutaneous adipose tissue	UBERON:0002190	95.26	gold quality
urethra	UBERON:0000057	95.10	gold quality
esophagus mucosa	UBERON:0002469	95.09	gold quality
nipple	UBERON:0002030	94.78	gold quality
upper arm skin	UBERON:0004263	94.50	gold quality
ectocervix	UBERON:0012249	94.45	gold quality
lower esophagus mucosa	UBERON:0035834	94.14	gold quality
vena cava	UBERON:0004087	93.58	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-HCAD-11	yes	502.43
E-HCAD-36	yes	389.67
E-MTAB-10287	yes	67.07
E-CURD-114	yes	54.54
E-HCAD-10	yes	42.83
E-GEOD-135922	yes	29.81
E-ANND-3	yes	26.90
E-MTAB-8410	yes	25.86
E-MTAB-6678	yes	13.65
E-GEOD-134144	yes	12.23
E-MTAB-5061	yes	11.72
E-CURD-46	yes	10.07
E-HCAD-35	yes	9.33
E-CURD-112	yes	8.21
E-ENAD-27	yes	7.14

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
APOD	Repression
ASPH	Unknown
HES1	Repression
HEY1	Activation
HEY2	Activation
HEYL	Activation

Upstream regulators (CollecTRI, top): CTCFL, ELF3, ERBB2, FOXO3, MEF2C, MSX1, MYOD1, PAX6, PAX7, PBX1, RBPJ, SMAD3, SSRP1, STAT3, TCF12

miRNA regulators (miRDB)

85 targeting NOTCH3, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-4271	99.88	68.32	2244

Literature-anchored findings (GeneRIF, showing 40)

• Results indicate that T6746C polymorphism in the intracellular domain of the Notch3 gene is not associated with increased risk for CVDD. (PMID:11861701)
• Combined expression of pTalpha and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis (PMID:11891328)
• Notch signalling involved in differentiation of normal adult human epidermis is altered under experimental conditions and pathologies which modify this program. (PMID:11978185)
• Notch3 does not appear to be a candidate gene for BPD in this family. (PMID:12210282)
• Polymorphism is not associated with cerebrovascular disease in Japanese patients. (PMID:12480758)
• Notch 3 gene is responsible for CADASIL among patients of different ethncis. (PMID:12678157)
• Genetic, clinical and pathological studies of CADASIL in Japan: a partial contribution of Notch3 mutations and implications of smooth muscle cell degeneration for the pathogenesis. (PMID:12810003)
• This is the first missense mutation in codon 1006 of exon 19 of the Notch3 gene to be described in Italy and the second reported in the literature. (PMID:14767686)
• Acute visual loss due to nonarteritic anterior ischemic optic neuropathy (NAION) has not previously been reported in CADASIL (heterozygotes for the C406T mutation on exon 3 of the Notch3 gene). (PMID:15096408)
• This 12-bp deletion in the extracellular domain mutation is the first CADASIL-associated Notch3 mutation not involving a cysteine residue in the EGF-like repats. (PMID:15304596)
• The mutation in position 133 (R133C) of the NOTCH3 gene, which maps to 19p13.1, is found in Finnish families with CADASIL. (PMID:15378071)
• Our findings emphasize the importance of genetic analysis of NOTCH3 for Asians with a phenotype typical of CADASIL. (PMID:15694192)
• Notch promotes changes in hVSMC phenotype via activation of CBF-1/RBP-Jkappa-dependent pathways in vitro and contributes to the phenotypic response of VSMCs to cyclic strain-induced changes in VSMC differentiation. (PMID:15987768)
• subtle abnormalities seen in furin processing of mutant Notch3 receptor, although both heterodimeric and full length receptors are present on cell surface, are capable of interacting with soluble forms of three ligands, and retain ability to activate CBF1 (PMID:16107360)
• Findings support the view that functional polymorphism T6746C in Notch3 gene is not involved in increasing the risk of migraine or migraine subtypes. (PMID:16492242)
• The novel Korean mutation of R75P, not involving a cysteine residue, is related to less frequent involvement of the anterior temporal area, thus broadening the spectrum of CADASIL. (PMID:16717210)
• a 44-year-old patient with clinical features of CADASIL who was a carrier of a new Notch3 mutation: cys128–>gly. (PMID:16796587)
• Our results show that mtDNA sequence variation is increased within CADASIL pedigrees. These findings suggest a relationship between NOTCH3 and mtDNA. (PMID:16807713)
• The defective gene in CADASIL is Notch 3, which encodes a large transmembrane receptor. (PMID:16833034)
• Italian CADASIL families from Central Italy with mutation CGC-TGC at codon 1006 in the exon 19 Notch3 gene. (PMID:16998728)
• Notch-3 expression is dysregulated in breast cancer. (PMID:17158237)
• Role for the conserved N-terminal sequence of Notch3: targeting of the protein to the secretory pathway and reduction of cytoplasmic Notch3 expression which may inhibit cytoplasmic functions. (PMID:17292860)
• with supervised resistance exercise training, expression of Notch1 and Hes6 genes were increased and Delta-like 1 and Numb expression were decreased. (PMID:17301032)
• A model that invokes novel pathogenic roles for the mutant NOTCH3 protein rather than compromised NOTCH3 function as the primary determinant of the CADASIL arteriopathy. (PMID:17331978)
• Genetic analysis of Notch3 revealed an R141C missense mutation and she was diagnosed with CADASIL complicated with IgA nephropathy. (PMID:17390743)
• NOTCHES N1, N2, and N3 all bound to FIH; results suggest the possibility that Notch ICDs are FIH substrates. (PMID:17573339)
• This study describe the genetical, clinical,neuropsychological and neuroimaging findings in an Italian CADASIL patient with a rare mutation in exon 10 leading to a Gly528Cys substitution. (PMID:17690848)
• Suggest an aberrant expression of Notch3 and Notch4 in HCC and allow the hypothesis of an activation of Notch signalling by Notch3. (PMID:17696940)
• Notch pathway plays an important role in lung cancer biology. (PMID:17804716)
• Overexpression of notch3 is associated with breast cancer (PMID:17822320)
• Notch3 promotes cell growth and survival by activating PI3-kinase/AKT pathway; N-cadherin participates in the change of cell growth caused by Notch3 activation; and Notch3 signalling has dual-effects on the Wnt/TCF pathway. (PMID:17822871)
• Results describe a Spanish family reported with CADASIL, caused by the 346C > T mutation in NOTCH3 gene. (PMID:17853970)
• This review focuses on recent findings of Notch3 in vascular development and in regulating vascular smooth muscle cell behavior and phenotype. (PMID:17854869)
• In CADASIL patients, Notch3 mutations were associated with mitochondrial disease, particularly affecting the skeletal muscle. (PMID:17878719)
• Cytoplasmic expression of Notch 3 receptors was detected and Notch signaling might be involved in development of hepatocellular carcinoma. (PMID:17920003)
• Rgs5 and Notch3 are expressed in pericytes of developing and injured teeth and have roles along with vascular-derived stem cells during pulp healing (PMID:17939118)
• Positive MRI findings in asymptomatic individuals or in-patients who presented with depression or a psychiatric problem indicated that NOTCH3 gene signalling may start early and may have different clinical presentations (PMID:17996090)
• We report for the first time a mutation on exon 21 of the NOTCH3 gene that leads to a cysteine substitution in the EGF-like repeat 29 of the NOTCH3 receptor extracellular domain, and that causes CADASIL in a functionally independent elderly man. (PMID:18022198)
• IL-6 treatment triggered Notch-3-dependent upregulation of the Notch ligand Jagged-1 and promotion of MS and MCF-7-derived spheroid growth (PMID:18060036)
• we conclude that in the ectatic ducts of CP, PDH activates signalling pathways such as Notch, which have transforming potential. (PMID:18069660)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	notch3	ENSDARG00000052139
mus_musculus	Notch3	ENSMUSG00000038146
rattus_norvegicus	Notch3	ENSRNOG00000004346

Paralogs (7): NOTCH2 (ENSG00000134250), NOTCH1 (ENSG00000148400), SNED1 (ENSG00000162804), NOTCH2NLA (ENSG00000264343), NOTCH2NLB (ENSG00000286019), NOTCH2NLR (ENSG00000286106), NOTCH2NLC (ENSG00000286219)

Protein

Protein identifiers

Neurogenic locus notch homolog protein 3 — Q9UM47 (reviewed: Q9UM47)

All UniProt accessions (4): Q9UM47, M0QX38, M0QZN3, M0R3C9

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 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.

Subunit / interactions. Heterodimer of a C-terminal fragment N(TM) and a N-terminal fragment N(EC) which are probably linked by disulfide bonds. Interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH3. Interacts with PSMA1. Interacts with HIF1AN.

Subcellular location. Cell membrane Nucleus.

Tissue specificity. Ubiquitously expressed in fetal and adult 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 TNF converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT). This fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane. Phosphorylated. Hydroxylated by HIF1AN.

Disease relevance. Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, 1 (CADASIL1) [MIM:125310] A cerebrovascular disease characterized by multiple subcortical infarcts, pseudobulbar palsy, dementia, and the presence of granular deposits in small cerebral arteries producing ischemic stroke. The disease is caused by variants affecting the gene represented in this entry. Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1 (CARASIL1) [MIM:621295] A cerebrovascular disease characterized by arteriopathy of cerebral small vessels and onset of neurologic symptoms in infancy or early childhood. Affected individuals present with periventricular or periatrial leukoencephalopathy, white matter lesions in the basal ganglia, microbleeds, enlarged ventricles, and white matter volume loss. Additional features include hypotonia, developmental delay, variably impaired intellectual development, spasticity, hyperreflexia, stoke, hemiparesis, seizures, coarse facial features, and strabismus. The disease is caused by variants affecting the gene represented in this entry. Myofibromatosis, infantile 2 (IMF2) [MIM:615293] A rare mesenchymal disorder characterized by the development of benign tumors in the skin, striated muscles, bones, and, more rarely, visceral organs. Subcutaneous or soft tissue nodules commonly involve the skin of the head, neck, and trunk. Skeletal and muscular lesions occur in about half of the patients. Lesions may be solitary or multicentric, and they may be present at birth or become apparent in early infancy or occasionally in adult life. Visceral lesions are associated with high morbidity and mortality. The gene represented in this entry may be involved in disease pathogenesis. Lateral meningocele syndrome (LMNS) [MIM:130720] A very rare skeletal disorder with facial anomalies, hypotonia and neurologic dysfunction due to meningocele, a protrusion of the meninges, unaccompanied by neural tissue, through a bony defect in the skull or vertebral column. LMNS facial features include hypertelorism and telecanthus, high arched eyebrows, ptosis, mid-facial hypoplasia, micrognathia, high and narrow palate, low-set ears and a hypotonic appearance. Additional variable features are connective tissue abnormalities, aortic dilation, a high-pitched nasal voice, wormian bones and osteolysis. The disease is caused by variants affecting the gene represented in this entry. Lipodystrophy, familial partial, 1 (FPLD1) [MIM:608600] A form of partial lipodystrophy, a disorder characterized by abnormal subcutaneous fat distribution. FPLD1 affected individuals have loss of subcutaneous adipose tissue from the upper and lower extremities, increased muscularity, and normal or increased distribution of fat in the trunk or abdomen. Patients develop metabolic complications including hypertriglyceridemia, hepatic steatosis, and insulin-dependent diabetes. FPLD1 is an autosomal dominant disorder with age-dependent penetrance. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. The EGF-like domains 10 and 11 are required for binding the ligands JAG1 and DLL1.

Similarity. Belongs to the NOTCH family.

RefSeq proteins (1): NP_000426* (*=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
IPR022331	Notch_3	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 (340 total): sequence variant 131, disulfide bond 111, domain 34, helix 17, strand 11, turn 8, repeat 8, compositionally biased region 5, chain 3, region of interest 3, glycosylation site 3, topological domain 2, signal peptide 1, transmembrane region 1, site 1, modified residue 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
5CZX	X-RAY DIFFRACTION	2.1
6WQU	X-RAY DIFFRACTION	2.41
4ZLP	X-RAY DIFFRACTION	2.48
6XSW	X-RAY DIFFRACTION	2.98
5CZV	X-RAY DIFFRACTION	3.19
8OS0	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UM47-F1	61.79	0.07

Antibody-complex structures (SAbDab): 3 — 5CZV, 5CZX, 6XSW

Functional residue map

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

Catalytic / active sites (1): 1571–1572 (cleavage; by furin-like protease)

Post-translational modifications (1): 2174

Disulfide bonds (111): 533–542, 549–559, 554–568, 570–579, 586–597, 591–606, 608–617, 624–634, 629–643, 645–654, 661–672, 666–681, 683–692, 699–709, 704–718, 720–729, 738–749, 743–758, 760–769, 775–786 …

Glycosylation sites (3): 1179, 1336, 1438

Function

Pathways and Gene Ontology

Reactome pathways

8 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-350054	Notch-HLH transcription pathway
R-HSA-5083630	Defective LFNG causes SCDO3
R-HSA-9013507	NOTCH3 Activation and Transmission of Signal to the Nucleus
R-HSA-9013508	NOTCH3 Intracellular Domain Regulates Transcription
R-HSA-9017802	Noncanonical activation of NOTCH3

MSigDB gene sets: 565 (showing top): REACTOME_SIGNALING_BY_NOTCH, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, PEREZ_TP63_TARGETS, CHIARETTI_T_ALL_REFRACTORY_TO_THERAPY, GOCC_CELL_SURFACE, KEGG_DORSO_VENTRAL_AXIS_FORMATION, SATO_SILENCED_BY_DEACETYLATION_IN_PANCREATIC_CANCER, GOBP_NEUROGENESIS, GOBP_ARTERY_DEVELOPMENT, GOBP_MUSCLE_CELL_PROLIFERATION, SP1_Q2_01, GOBP_FOREBRAIN_DEVELOPMENT, TTGGGAG_MIR150, PATIL_LIVER_CANCER, GOBP_POSITIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION

GO Biological Process (19): negative regulation of transcription by RNA polymerase II (GO:0000122), Notch signaling pathway (GO:0007219), axon guidance (GO:0007411), neuroblast differentiation (GO:0014016), forebrain development (GO:0030900), negative regulation of neuron differentiation (GO:0045665), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of smooth muscle cell proliferation (GO:0048661), neuron fate commitment (GO:0048663), artery morphogenesis (GO:0048844), glomerular capillary formation (GO:0072104), positive regulation of miRNA transcription (GO:1902895), regulation of DNA-templated transcription (GO:0006355), multicellular organism development (GO:0007275), cell differentiation (GO:0030154), neuron differentiation (GO:0030182), negative regulation of cell differentiation (GO:0045596), positive regulation of DNA-templated transcription (GO:0045893), regulation of developmental process (GO:0050793)

GO Molecular Function (6): calcium ion binding (GO:0005509), enzyme binding (GO:0019899), signaling receptor activity (GO:0038023), identical protein binding (GO:0042802), cadherin binding (GO:0045296), protein binding (GO:0005515)

GO Cellular Component (11): Golgi membrane (GO:0000139), extracellular region (GO:0005576), nucleoplasm (GO:0005654), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), signaling receptor complex (GO:0043235), nucleus (GO:0005634), membrane (GO:0016020), cell periphery (GO:0071944)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Pre-NOTCH Expression and Processing	3
Signaling by NOTCH3	2
Generic Transcription Pathway	1
Diseases associated with O-glycosylation of proteins	1
NOTCH3 Activation and Transmission of Signal to the Nucleus	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cell differentiation	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
generation of neurons	2
anatomical structure development	2
neuron differentiation	2
positive regulation of DNA-templated transcription	2
DNA-templated transcription	2
protein binding	2
negative regulation of DNA-templated transcription	1
cell surface receptor signaling pathway	1
axonogenesis	1
neuron projection guidance	1
brain development	1
negative regulation of cell differentiation	1
regulation of neuron differentiation	1
positive regulation of cell population proliferation	1
smooth muscle cell proliferation	1
regulation of smooth muscle cell proliferation	1
cell fate commitment	1
blood vessel morphogenesis	1
artery development	1
angiogenesis	1
glomerulus vasculature morphogenesis	1
miRNA transcription	1
regulation of miRNA transcription	1
positive regulation of miRNA metabolic process	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
multicellular organismal process	1
cellular developmental process	1
regulation of cell differentiation	1
negative regulation of cellular process	1
negative regulation of developmental process	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
developmental process	1
regulation of biological process	1
metal ion binding	1

Protein interactions and networks

STRING

4121 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NOTCH3	JAG1	P78504	988
NOTCH3	DLL1	O00548	988
NOTCH3	JAG2	Q9Y219	988
NOTCH3	DLL4	Q9NR61	987
NOTCH3	DLL3	Q9NYJ7	982
NOTCH3	RBPJ	Q06330	917
NOTCH3	HES5	Q5TA89	865
NOTCH3	MAML3	Q96JK9	863
NOTCH3	MAML1	Q92585	842
NOTCH3	MAML2	Q8IZL2	787
NOTCH3	HEY1	Q9Y5J3	784
NOTCH3	PDGFRB	P09619	730
NOTCH3	SRRT	Q9BXP5	723
NOTCH3	TP53	P04637	710
NOTCH3	HEY2	Q9UBP5	705

IntAct

118 interactions, top by confidence:

A	B	Type	Score
RBPJ	NOTCH1	psi-mi:“MI:0914”(association)	0.910
HIF1AN	APBA3	psi-mi:“MI:0914”(association)	0.850
ANKRD44	PPP6C	psi-mi:“MI:0914”(association)	0.790
ANKRD44	ANKRD28	psi-mi:“MI:0914”(association)	0.710
HIF1AN	GMDS	psi-mi:“MI:0914”(association)	0.640
SLC20A1	LIN7A	psi-mi:“MI:0914”(association)	0.640
SLC12A2	CLGN	psi-mi:“MI:0914”(association)	0.640
NOTCH3	NOTCH3	psi-mi:“MI:0407”(direct interaction)	0.560
PRR20D	NOTCH3	psi-mi:“MI:0915”(physical association)	0.560
RABGGTB	PIPSL	psi-mi:“MI:0914”(association)	0.530
MANSC1	KLRG2	psi-mi:“MI:0914”(association)	0.530
TSPAN3	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.530
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
ZNF224	LRP4	psi-mi:“MI:0914”(association)	0.530
ADAM33	LRP5	psi-mi:“MI:0914”(association)	0.530
BTNL3	FAM171A2	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
ZFP41	LRP4	psi-mi:“MI:0914”(association)	0.530
ZNF408	LRP4	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
LGALS1	LAMA5	psi-mi:“MI:0914”(association)	0.530

BioGRID (164): MPPED2 (Reconstituted Complex), GGT6 (Reconstituted Complex), CBFA2T2 (Reconstituted Complex), SPTLC2 (Reconstituted Complex), RET (Reconstituted Complex), MYC (Reconstituted Complex), SORBS3 (Reconstituted Complex), WWP2 (Reconstituted Complex), RBPJ (Reconstituted Complex), TNNT2 (Reconstituted Complex), XKR8 (Reconstituted Complex), SNX19 (Reconstituted Complex), CNTD1 (Reconstituted Complex), WDR25 (Reconstituted Complex), SCGB3A1 (Reconstituted Complex)

ESM2 similar proteins: A0A096LNW5, A2RUV0, A8XMW6, B8JI71, D3ZHH1, G3I6Z6, O35516, O57409, O70244, P07207, P0DPK3, P10040, P10079, P21783, P34576, P35442, P46530, P46531, P49013, P78504, P97607, P97677, Q01705, Q03350, Q04721, Q07008, Q5ZQU0, Q61483, Q61982, Q63722, Q6DI48, Q70E20, Q7Z3S9, Q8JZM4, Q8NFT8, Q8TER0, Q8UWJ4, Q90Y54, Q90Y57, Q95116

Diamond homologs: A0A084B9Z8, B4E2M5, P42773, Q03017, Q4FE45, Q4JHE0, Q502M6, Q60772, Q61982, Q6RI86, Q8BLA8, Q9R172, Q9UM47, A0A096LNW5, A2RUV0, B4DH59, B8JI71, G3I6Z6, O35516, O75882, P07207, P0DPK3, P0DPK4, P10040, P21783, P46530, P46531, P98160, Q01705, Q04721, Q04756, Q07008, Q20911, Q7Z3S9, Q99466, Q99J86, Q9QW30, Q9WU60, O35474, O75095

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
ERBB2	“up-regulates quantity by expression”	NOTCH3	“transcriptional regulation”
NOTCH3	“up-regulates quantity by expression”	HES1	“transcriptional regulation”
JAG1	up-regulates	NOTCH3	binding
TCF12	“up-regulates quantity by expression”	NOTCH3	“transcriptional regulation”
gamma-secretase	“up-regulates activity”	NOTCH3	cleavage
EGFR	“up-regulates activity”	NOTCH3	phosphorylation
DLL1	up-regulates	NOTCH3	binding
JAG2	up-regulates	NOTCH3	binding
NOTCH3	“up-regulates quantity by expression”	HEYL	“transcriptional regulation”
MAML1	up-regulates	NOTCH3	binding
NOTCH3	up-regulates	RBPJ	binding
MAML3	up-regulates	NOTCH3	binding
FOXO3	“down-regulates quantity”	NOTCH3	“transcriptional regulation”
FOXO	“down-regulates quantity”	NOTCH3	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 127 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
Constitutive Signaling by NOTCH1 PEST Domain Mutants	5	12.3×	4e-03
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	5	12.3×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of cell adhesion	5	17.7×	2e-03
regulation of mitotic cell cycle	5	11.2×	1e-02
Notch signaling pathway	8	10.5×	4e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

2051 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	169
Likely pathogenic	91
Uncertain significance	829
Likely benign	435
Benign	132

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1064640	NM_000435.3(NOTCH3):c.967T>A (p.Cys323Ser)	Pathogenic
1175947	NM_000435.3(NOTCH3):c.581G>T (p.Cys194Phe)	Pathogenic
1256484	NM_000435.3(NOTCH3):c.1241C>G (p.Ser414Cys)	Pathogenic
1256492	NM_000435.3(NOTCH3):c.1736G>A (p.Cys579Tyr)	Pathogenic
1256502	NM_000435.3(NOTCH3):c.244T>C (p.Cys82Arg)	Pathogenic
1256516	NM_000435.3(NOTCH3):c.3925C>T (p.Arg1309Cys)	Pathogenic
1256528	NM_000435.3(NOTCH3):c.553T>G (p.Cys185Gly)	Pathogenic
1256529	NM_000435.3(NOTCH3):c.566A>G (p.Tyr189Cys)	Pathogenic
1256530	NM_000435.3(NOTCH3):c.581G>A (p.Cys194Tyr)	Pathogenic
1256533	NM_000435.3(NOTCH3):c.602G>C (p.Cys201Ser)	Pathogenic
1256542	NM_000435.3(NOTCH3):c.955_956delinsTG (p.Ala319Cys)	Pathogenic
1298355	NM_000435.3(NOTCH3):c.1492G>T (p.Gly498Cys)	Pathogenic
1328242	NM_000435.3(NOTCH3):c.1591T>G (p.Cys531Gly)	Pathogenic
1471082	NM_000435.3(NOTCH3):c.730C>T (p.Arg244Ter)	Pathogenic
161467	NM_000435.3(NOTCH3):c.146G>T (p.Cys49Phe)	Pathogenic
1701358	NM_000435.3(NOTCH3):c.484T>C (p.Cys162Arg)	Pathogenic
1709532	NM_000435.3(NOTCH3):c.2963G>A (p.Cys988Tyr)	Pathogenic
1709694	NM_000435.3(NOTCH3):c.547T>A (p.Cys183Ser)	Pathogenic
1709971	NM_000435.3(NOTCH3):c.699T>G (p.Cys233Trp)	Pathogenic
1807351	NM_000435.3(NOTCH3):c.1282T>C (p.Cys428Arg)	Pathogenic
1807353	NM_000435.3(NOTCH3):c.213G>C (p.Trp71Cys)	Pathogenic
1807362	NM_000435.3(NOTCH3):c.278G>A (p.Cys93Tyr)	Pathogenic
1807364	NM_000435.3(NOTCH3):c.128_129delinsAT (p.Cys43Tyr)	Pathogenic
1807365	NM_000435.3(NOTCH3):c.2798G>T (p.Cys933Phe)	Pathogenic
1807381	NM_000435.3(NOTCH3):c.1533C>G (p.Cys511Trp)	Pathogenic
1807383	NM_000435.3(NOTCH3):c.1646G>C (p.Cys549Ser)	Pathogenic
1807385	NM_000435.3(NOTCH3):c.3628C>T (p.Arg1210Cys)	Pathogenic
1807386	NM_000435.3(NOTCH3):c.502T>A (p.Cys168Ser)	Pathogenic
1807387	NM_000435.3(NOTCH3):c.664T>C (p.Cys222Arg)	Pathogenic
1807398	NM_000435.3(NOTCH3):c.199T>A (p.Cys67Ser)	Pathogenic

SpliceAI

4436 predictions. Top by Δscore:

Variant	Effect	Δscore
19:15161715:C:CG	acceptor_loss	1.0000
19:15162459:GCTCA:G	donor_loss	1.0000
19:15162460:CTCA:C	donor_loss	1.0000
19:15162461:TCA:T	donor_loss	1.0000
19:15162462:CA:C	donor_loss	1.0000
19:15162463:ACCTT:A	donor_loss	1.0000
19:15162558:TTTCC:T	acceptor_gain	1.0000
19:15162559:TTCC:T	acceptor_gain	1.0000
19:15162560:TCC:T	acceptor_gain	1.0000
19:15162560:TCCC:T	acceptor_loss	1.0000
19:15162561:CC:C	acceptor_gain	1.0000
19:15162561:CCC:C	acceptor_gain	1.0000
19:15162562:CC:C	acceptor_gain	1.0000
19:15162563:C:CA	acceptor_loss	1.0000
19:15162563:C:CC	acceptor_gain	1.0000
19:15162564:T:C	acceptor_loss	1.0000
19:15165363:CCTA:C	donor_loss	1.0000
19:15165364:CTA:C	donor_loss	1.0000
19:15165365:TA:T	donor_loss	1.0000
19:15165366:A:AC	donor_gain	1.0000
19:15165366:ACCAA:A	donor_loss	1.0000
19:15165367:C:CC	donor_gain	1.0000
19:15165367:CCAAG:C	donor_gain	1.0000
19:15165511:AGAAT:A	acceptor_gain	1.0000
19:15165514:AT:A	acceptor_gain	1.0000
19:15165515:TCTAG:T	acceptor_loss	1.0000
19:15165516:C:CC	acceptor_gain	1.0000
19:15165781:TCTCA:T	donor_loss	1.0000
19:15165782:CTCA:C	donor_loss	1.0000
19:15165783:TCACC:T	donor_loss	1.0000

AlphaMissense

15057 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:15161704:G:T	P1975H	1.000
19:15162502:A:G	L1959P	1.000
19:15162505:A:G	L1958P	1.000
19:15162543:C:A	W1945C	1.000
19:15162543:C:G	W1945C	1.000
19:15162545:A:G	W1945R	1.000
19:15162545:A:T	W1945R	1.000
19:15165409:A:G	L1925P	1.000
19:15165409:A:T	L1925H	1.000
19:15165442:G:T	A1914D	1.000
19:15165511:A:G	L1891P	1.000
19:15165815:A:T	V1880D	1.000
19:15165818:G:T	A1879D	1.000
19:15165830:G:T	P1875H	1.000
19:15165881:A:G	L1858P	1.000
19:15165890:G:T	A1855D	1.000
19:15165914:G:T	A1847D	1.000
19:15165920:A:G	L1845P	1.000
19:15167361:C:A	W1750C	1.000
19:15167361:C:G	W1750C	1.000
19:15167363:A:G	W1750R	1.000
19:15167363:A:T	W1750R	1.000
19:15174319:C:A	W1495C	1.000
19:15174319:C:G	W1495C	1.000
19:15177653:C:A	W1425C	1.000
19:15177653:C:G	W1425C	1.000
19:15189004:A:G	C455R	1.000
19:15189063:C:G	C435S	1.000
19:15189064:A:T	C435S	1.000
19:15189084:C:G	C428S	1.000

dbSNP variants (sampled 300 via entrez): RS1000054521 (19:15193799 A>G), RS1000139397 (19:15169228 C>T), RS1000251334 (19:15199404 G>A), RS1000336893 (19:15187311 T>A,C), RS1000398497 (19:15174805 C>A), RS1000421145 (19:15193605 A>C,G), RS1000425845 (19:15181986 C>A), RS1000503679 (19:15170239 G>C), RS1000587671 (19:15168950 G>A,T), RS1000616473 (19:15163428 A>G), RS1000705144 (19:15176704 A>G), RS1000723280 (19:15169263 G>A,C), RS1000748927 (19:15163029 T>A,G), RS1000769272 (19:15199701 T>A,C,G), RS1000769662 (19:15175036 C>G)

Disease associations

OMIM: gene MIM:600276 | disease phenotypes: MIM:125310, MIM:130720, MIM:615293, MIM:182410, MIM:621295, MIM:609129, MIM:608600, MIM:616028, MIM:228550

GenCC curated gene-disease

Disease	Classification	Inheritance
cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Definitive	Autosomal dominant
lateral meningocele syndrome	Strong	Autosomal dominant
infantile myofibromatosis	Supportive	Autosomal dominant
myofibromatosis, infantile, 2	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
inherited thrombocytopenia	Limited	AR
pulmonary arterial hypertension	Disputed	AD

Mondo (25): cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (MONDO:0000914), cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (MONDO:0007432), lateral meningocele syndrome (MONDO:0007537), myofibromatosis, infantile, 2 (MONDO:0014122), cerebral cavernous malformation (MONDO:0000820), Sneddon syndrome (MONDO:0008436), pulmonary arterial hypertension (MONDO:0015924), prostate cancer (MONDO:0008315), transient ischemic attack (MONDO:0005264), ischemic stroke (MONDO:1060198), breast ductal adenocarcinoma (MONDO:0005590), vascular parkinsonism (MONDO:0956980), cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1 (MONDO:0979867), auditory neuropathy (MONDO:0021944), cerebral arterial disease (MONDO:0006693)

Orphanet (11): Cerebral autosomal dominant arteriopathy-subcortical infarcts-leukoencephalopathy (Orphanet:136), Infantile myofibromatosis (Orphanet:2591), Lateral meningocele syndrome (Orphanet:2789), Familial cerebral cavernous malformation (Orphanet:221061), Sneddon syndrome (Orphanet:820), Pulmonary arterial hypertension (Orphanet:182090), Familial prostate cancer (Orphanet:1331), Familial partial lipodystrophy, Köbberling type (Orphanet:79084), Adams-Oliver syndrome (Orphanet:974), NON RARE IN EUROPE: Cerebral cavernous malformations (Orphanet:164), Idiopathic/heritable pulmonary arterial hypertension (Orphanet:422)

HPO phenotypes

295 total (30 of 295 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000020	Urinary incontinence
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000077	Abnormality of the kidney
HP:0000169	Gingival fibromatosis
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000268	Dolichocephaly
HP:0000271	Abnormality of the face
HP:0000272	Malar flattening
HP:0000275	Narrow face
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000287	Increased facial adipose tissue
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST007096_49	Pulse pressure	4.000000e-16
GCST007097_10	Pulse pressure	6.000000e-11
GCST007097_9	Pulse pressure	9.000000e-07
GCST007269_136	Pulse pressure	6.000000e-14
GCST90006927_3	Toxoplasma gondii sag1 antibody levels	4.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005763	pulse pressure measurement
EFO:0009353	Anti-Toxoplasma gondii IgG measurement

MeSH disease descriptors (17)

Descriptor	Name	Tree numbers
D046589	CADASIL	C10.228.140.300.150.477.200.100; C10.228.140.300.275.249; C10.228.140.300.400.203; C10.228.140.300.510.200.175; C10.228.140.300.775.200.200.100; C10.228.140.380.230.124; C14.907.253.092.477.200.100; C14.907.253.329.249; C14.907.253.560.200.175; C14.907.253.855.200.200.100; C16.320.129; C23.550.513.355.250.200.100; C23.550.717.489.250.200.100
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D002539	Cerebral Arterial Diseases	C10.228.140.300.510.200; C14.907.253.560.200
D015140	Dementia, Vascular	C10.228.140.300.400; C10.228.140.300.510.800.500; C10.228.140.380.230; C10.228.140.695.500; C14.907.137.126.372.500; C14.907.253.560.350.500; F03.615.400.350
D003866	Depressive Disorder	F03.600.300
D002546	Ischemic Attack, Transient	C10.228.140.300.150.836; C14.907.253.092.836
D008881	Migraine Disorders	C10.228.140.546.399.750
D020325	Migraine with Aura	C10.228.140.546.399.750.250
D020326	Migraine without Aura	C10.228.140.546.399.750.450
D018224	Myofibromatosis	C04.557.450.565.590.550
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
D000081029	Pulmonary Arterial Hypertension	C08.381.423.847
D018860	Sneddon Syndrome	C10.228.140.300.750; C14.907.253.774; C17.800.862.775
D020521	Stroke	C10.228.140.300.775; C14.907.253.855
C538268	Auditory neuropathy (supp.)
C562978	Fibromatosis, Congenital Generalized (supp.)
C537878	Lateral meningocele syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3407319 (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

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 (1 total), top 1:

Ligand	Action	Affinity	Parameter
tarextumab	Binding	9.92	pKd

Binding affinities (BindingDB)

64 measured of 64 human assays (64 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

57 potent at pChembl≥5 of 57 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL3410162
9.00	IC50	1	nM	CHEMBL3410153
9.00	IC50	1	nM	CHEMBL3410167
9.00	IC50	1	nM	CHEMBL3410169
8.85	IC50	1.4	nM	CHEMBL3908473
8.72	IC50	1.9	nM	CHEMBL3896661
8.70	IC50	2	nM	CHEMBL3410163
8.70	IC50	2	nM	CHEMBL3410168
8.70	IC50	2	nM	CHEMBL3410170
8.68	IC50	2.1	nM	CHEMBL3922868
8.62	IC50	2.4	nM	CHEMBL3948923
8.57	IC50	2.7	nM	CHEMBL3973748
8.54	IC50	2.9	nM	CHEMBL3929363
8.52	IC50	3	nM	CHEMBL3410160
8.52	IC50	3	nM	CHEMBL3410152
8.52	IC50	3	nM	CHEMBL3410151
8.52	IC50	3	nM	CHEMBL3971963
8.49	IC50	3.2	nM	CHEMBL3984723
8.47	IC50	3.4	nM	CHEMBL3935299
8.43	IC50	3.7	nM	CHEMBL3913200
8.43	IC50	3.7	nM	CHEMBL3949951
8.40	IC50	4	nM	CHEMBL3410161
8.40	IC50	4	nM	CHEMBL3410164
8.40	IC50	4	nM	CHEMBL3915833
8.40	IC50	4	nM	CHEMBL3985392
8.38	IC50	4.2	nM	CHEMBL3960841
8.37	IC50	4.3	nM	CHEMBL3984405
8.36	IC50	4.4	nM	CHEMBL3891599
8.36	IC50	4.4	nM	CHEMBL3923405
8.35	IC50	4.5	nM	CHEMBL3985584
8.34	IC50	4.6	nM	CHEMBL3984170
8.31	IC50	4.9	nM	CHEMBL3983707
8.27	IC50	5.4	nM	CHEMBL3944645
8.24	IC50	5.7	nM	CHEMBL3895390
8.22	IC50	6	nM	CHEMBL3410166
8.21	IC50	6.1	nM	CHEMBL3919904
8.21	IC50	6.1	nM	CHEMBL3955547
8.20	IC50	6.3	nM	CHEMBL3938447
8.14	IC50	7.3	nM	CHEMBL3893305
8.14	IC50	7.2	nM	CHEMBL3944272
8.13	IC50	7.4	nM	CHEMBL3909875
8.11	IC50	7.7	nM	CHEMBL3965388
8.10	IC50	7.9	nM	CHEMBL3960841
8.08	IC50	8.3	nM	CHEMBL3950601
8.07	IC50	8.5	nM	VAREGACESTAT
8.03	IC50	9.3	nM	CHEMBL3903119
7.94	IC50	11.6	nM	CHEMBL3977486
7.90	IC50	12.6	nM	CHEMBL3965328
7.87	IC50	13.4	nM	CHEMBL3983168
7.82	IC50	15	nM	CHEMBL3913200

PubChem BioAssay actives

20 with measured affinity, of 20 total; 20 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	1198934: Inhibition of Notch3 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-methylphenyl)-3-(3,3,3-trifluoropropyl)butanediamide	1198934: Inhibition of Notch3 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	1198934: Inhibition of Notch3 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-(4-fluorophenyl)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	1198934: Inhibition of Notch3 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	1198934: Inhibition of Notch3 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-(3,4-difluorophenyl)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	1198934: Inhibition of Notch3 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	1198934: Inhibition of Notch3 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	1198934: Inhibition of Notch3 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0030	uM
(2S,3R)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-3-(2-methylpropyl)-2-pentan-3-ylbutanediamide	1198934: Inhibition of Notch3 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)-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	1198934: Inhibition of Notch3 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	1198934: Inhibition of Notch3 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)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-2-phenyl-3-(3,3,3-trifluoropropyl)butanediamide	1198934: Inhibition of Notch3 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	1198934: Inhibition of Notch3 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0060	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	1198934: Inhibition of Notch3 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0240	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	1198934: Inhibition of Notch3 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0290	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	1198934: Inhibition of Notch3 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0620	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	1198934: Inhibition of Notch3 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.1190	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	1198934: Inhibition of Notch3 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.1610	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	1198934: Inhibition of Notch3 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.6560	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	1198934: Inhibition of Notch3 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	2.2410	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, increases expression	3
bisphenol A	affects cotreatment, increases methylation, decreases expression	2
MRK 003	decreases response to substance, increases response to substance	2
Air Pollutants	decreases expression, increases abundance, affects methylation	2
Silicon Dioxide	decreases expression, decreases methylation	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects methylation	2
aristolochic acid I	increases expression	1
6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine	decreases expression	1
aminomethylphosphonic acid (AMPA)	decreases expression	1
captax	decreases expression	1
lauryl gallate	increases expression	1
salinomycin	decreases expression	1
5-chloro-2-methyl-4-isothiazolin-3-one	increases expression	1
cinnamaldehyde	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sulforaphane	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
pyrrolidine dithiocarbamic acid	decreases reaction, affects cotreatment, decreases expression	1
benzo(e)pyrene	decreases methylation	1
ferrous chloride	decreases expression	1
aflatoxin B2	decreases methylation	1
coumarin	decreases phosphorylation	1
tetrachloroplatinate	increases expression	1
diallyl trisulfide	decreases expression	1
gardenoside	affects binding, decreases reaction, decreases expression	1
picene	increases expression	1
pentabromodiphenyl ether	decreases expression	1
azoxystrobin	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3412051	Binding	Inhibition of Notch3 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	BMS-871: a novel orally active pan-Notch inhibitor as an anticancer agent. — Bioorg Med Chem Lett

Cellosaurus cell lines

24 cell lines: 12 cancer cell line, 6 induced pluripotent stem cell, 5 transformed cell line, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_6297	TTA-1	Cancer cell line	Male
CVCL_B7YJ	Abcam Raji NOTCH3 KO	Cancer cell line	Male
CVCL_B9Z8	Abcam THP-1 NOTCH3 KO	Cancer cell line	Male
CVCL_C5Z2	NCC-PS1-C1	Cancer cell line	Female
CVCL_C7AX	Abcam PC-3 NOTCH3 KO	Cancer cell line	Male
CVCL_D7W0	Ubigene A-549 NOTCH3 KO	Cancer cell line	Male
CVCL_D8RL	Ubigene HCT 116 NOTCH3 KO	Cancer cell line	Male
CVCL_D9LG	Ubigene HEK293 NOTCH3 KO	Transformed cell line	Female
CVCL_E0JA	Ubigene HeLa NOTCH3 KO	Cancer cell line	Female
CVCL_E0VT	Ubigene Huh-7 NOTCH3 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00058929	PHASE4	COMPLETED	A Transition Study From Flolan® to Remodulin® in Patients With Pulmonary Arterial Hypertension
NCT00303459	PHASE4	COMPLETED	Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH)
NCT00323297	PHASE4	COMPLETED	Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension
NCT00367770	PHASE4	COMPLETED	BREATHE 5-OL: Tracleer (Bosentan) in Patients With Pulmonary Arterial Hypertension Related to Eisenmenger Physiology
NCT00403650	PHASE4	COMPLETED	Inhaled Iloprost for Sarcoidosis-associated Pulmonary Hypertension
NCT00430716	PHASE4	TERMINATED	To Assess The Efficacy and Safety Of Oral Sildenafil in the Treatment of Pulmonary Arterial Hypertension.
NCT00433329	PHASE4	COMPLETED	Combination Therapy in Pulmonary Arterial Hypertension
NCT00439946	PHASE4	TERMINATED	Safety, Efficacy, and Treatment Satisfaction Switching From Flolan to Remodulin Using the Crono Five Ambulatory Pump in Patients With PAH
NCT00483626	PHASE4	UNKNOWN	Hemodynamic Response After Six Months of Sildenafil
NCT00494533	PHASE4	TERMINATED	Study of Intravenous Remodulin in Patients in India With Pulmonary Arterial Hypertension
NCT00617305	PHASE4	COMPLETED	Study of Add-on Ambrisentan Therapy to Background Phosphodiesterase Type-5 Inhibitor (PDE5i) Therapy in Pulmonary Arterial Hypertension (ATHENA-1)
NCT00625079	PHASE4	WITHDRAWN	Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis And Treatment With Sildenafil
NCT00625469	PHASE4	WITHDRAWN	Pulmonary Arterial Hypertension Secondary to Idiopathic Pulmonary Fibrosis and Treatment With Bosentan
NCT00705588	PHASE4	UNKNOWN	Long Acting Phosphodiesterase 5 Inhibitors as Add-on Therapy for Patients With Pulmonary Hypertension Treated With Prostanoids.
NCT00741819	PHASE4	COMPLETED	Safety Evaluation of Inhaled Treprostinil Administration Following Transition From Inhaled Ventavis in Pulmonary Arterial Hypertension (PAH) Subjects
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT01105091	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension
NCT01105117	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension - Extension of AC-066A401
NCT01268553	PHASE4	COMPLETED	Transition From Injectable Prostacyclin Medication to Inhaled Prostacyclin Medication
NCT01302444	PHASE4	TERMINATED	Treprostinil Combined With Tadalafil for Pulmonary Hypertension
NCT01330108	PHASE4	COMPLETED	Safely Change From Bosentan to Ambrisentan in Pulmonary Hypertension
NCT01433328	PHASE4	TERMINATED	Lidocaine Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01508780	PHASE4	WITHDRAWN	Combined Use of Angiography, Optical Coherence Tomography and Intravascular Ultrasound in Evaluation of Pulmonary Vascular Structure and Function in Patients With Pulmonary Arterial Hypertension Treated With Oral Bosentan
NCT01615627	PHASE4	WITHDRAWN	Hypotonic Treprostinil Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01642407	PHASE4	COMPLETED	Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension
NCT01649739	PHASE4	UNKNOWN	Vardenafil as add-on Therapy for Patients With Pulmonary Hypertension Treated With Inhaled Iloprost
NCT02060487	PHASE4	TERMINATED	Effects of Oral Sildenafil on Mortality in Adults With PAH
NCT02253394	PHASE4	TERMINATED	The Combination Ambrisentan Plus Spironolactone in Pulmonary Arterial Hypertension Study
NCT02284737	PHASE4	TERMINATED	A Study to Investigate the Efficacy of PADN to Improved Functional Capacity and Hemodynamics in Patients With PAH
NCT02310672	PHASE4	COMPLETED	REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension
NCT02847260	PHASE4	COMPLETED	Safety and Tolerability of Rapid Dose Titration of Subcutaneous Remodulin® Therapy in PAH Subjects (RAPID)
NCT02882126	PHASE4	WITHDRAWN	An Open Label Extension Study to Evaluate the Safety of Continued Therapy of Subcutanous Remodulin® in Pulmonary Arterial Hypertension
NCT02885012	PHASE4	TERMINATED	Crossover Study From Macitentan or Bosentan Over to Ambrisentan
NCT02891850	PHASE4	COMPLETED	Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy
NCT02893995	PHASE4	WITHDRAWN	Safety, Tolerability, Pharmacokinetics and Efficacy of Two Different Rates of Subcutanous Remodulin® Dose Titration in Pulmonary Arterial Hypertension
NCT02968901	PHASE4	TERMINATED	Clinical Study Evaluating the Effects of First-line Oral cOmbination theraPy of maciTentan and tadalafIl in Patients With Newly Diagnosed pulMonary Arterial Hypertension (OPTIMA)
NCT03055221	PHASE4	COMPLETED	TRUST-2: Safety and Efficacy of Intravenous Remodulin® in Patients in India With Pulmonary Arterial Hypertension (PAH)
NCT03078907	PHASE4	COMPLETED	Effect of Selexipag on Daily Life Physical Activity of Patients With Pulmonary Arterial Hypertension.
NCT03236818	PHASE4	UNKNOWN	Goal Oriented Strategy to Preserve Ejection Fraction Trial
NCT03344159	PHASE4	COMPLETED	Spironolactone Therapy in Chronic Stable Right HF Trial