RBPJ

Summary

RBPJ (recombination signal binding protein for immunoglobulin kappa J region, HGNC:5724) is a protein-coding gene on chromosome 4p15.2, encoding Recombining binding protein suppressor of hairless (Q06330). Transcriptional regulator that plays a central role in Notch signaling, a signaling pathway involved in cell-cell communication that regulates a broad spectrum of cell-fate determinations.

The protein encoded by this gene is a transcriptional regulator important in the Notch signaling pathway. The encoded protein acts as a repressor when not bound to Notch proteins and an activator when bound to Notch proteins. It is thought to function by recruiting chromatin remodeling complexes containing histone deacetylase or histone acetylase proteins to Notch signaling pathway genes. Several transcript variants encoding different isoforms have been found for this gene, and several pseudogenes of this gene exist on chromosome 9.

Source: NCBI Gene 3516 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Adams-Oliver syndrome 3 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 37
• Clinical variants (ClinVar): 214 total — 1 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 57
• Druggable target: yes
• Transcription factor: yes — 161 downstream targets (CollecTRI)
• MANE Select transcript: NM_015874

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5724
Approved symbol	RBPJ
Name	recombination signal binding protein for immunoglobulin kappa J region
Location	4p15.2
Locus type	gene with protein product
Status	Approved
Aliases	SUH, IGKJRB, RBPJK, KBF2, RBP-J, CBF1
Ensembl gene	ENSG00000168214
Ensembl biotype	protein_coding
OMIM	147183
Entrez	3516

Gene structure

Transcript identifiers

Ensembl transcripts: 57 — 35 protein_coding, 10 nonsense_mediated_decay, 9 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000342295, ENST00000342320, ENST00000345843, ENST00000348160, ENST00000355476, ENST00000361572, ENST00000504423, ENST00000504907, ENST00000504938, ENST00000505727, ENST00000505958, ENST00000506903, ENST00000506956, ENST00000507561, ENST00000507574, ENST00000509158, ENST00000510725, ENST00000510778, ENST00000511401, ENST00000511451, ENST00000511546, ENST00000512351, ENST00000512671, ENST00000513182, ENST00000514380, ENST00000514656, ENST00000514675, ENST00000514730, ENST00000514807, ENST00000515023, ENST00000515573, ENST00000679469, ENST00000679698, ENST00000680140, ENST00000680204, ENST00000680210, ENST00000680511, ENST00000680928, ENST00000681025, ENST00000681093, ENST00000681260, ENST00000681264, ENST00000681403, ENST00000681484, ENST00000681506, ENST00000681679, ENST00000681799, ENST00000681856, ENST00000689192, ENST00000691085, ENST00000692303, ENST00000892727, ENST00000892728, ENST00000914588, ENST00000914589, ENST00000914590, ENST00000962333

RefSeq mRNA: 13 — MANE Select: NM_015874 NM_001363577, NM_001374400, NM_001374401, NM_001374402, NM_001374403, NM_001379406, NM_001379407, NM_001379408, NM_001379409, NM_005349, NM_015874, NM_203283, NM_203284

CCDS: CCDS33969, CCDS3437, CCDS43219, CCDS87214

Canonical transcript exons

ENST00000355476 — 11 exons

Exon	Start	End
ENSE00001122445	26430419	26430522
ENSE00001122452	26429898	26430053
ENSE00001150902	26430692	26434923
ENSE00003469446	26406175	26406270
ENSE00003531672	26428720	26428860
ENSE00003553973	26424631	26424743
ENSE00003633263	26415475	26415640
ENSE00003651152	26386353	26386391
ENSE00003784978	26424342	26424479
ENSE00003786857	26420551	26420725
ENSE00003914859	26321014	26321048

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.4519 / max 1227.7753, expressed in 1806 samples.

FANTOM5 promoters (23 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47174	25.6905	1763
47173	14.8802	1774
47171	3.5817	1098
203127	0.7400	352
203125	0.5994	247
47169	0.5290	278
47183	0.4781	69
47175	0.3900	187
47182	0.3725	68
47177	0.3395	105

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
inferior olivary complex	UBERON:0002127	99.11	gold quality
nipple	UBERON:0002030	98.96	gold quality
calcaneal tendon	UBERON:0003701	98.96	gold quality
corpus callosum	UBERON:0002336	98.71	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	98.70	gold quality
middle temporal gyrus	UBERON:0002771	98.67	gold quality
synovial joint	UBERON:0002217	98.59	gold quality
tendon	UBERON:0000043	98.52	gold quality
inferior vagus X ganglion	UBERON:0005363	98.51	gold quality
pericardium	UBERON:0002407	98.50	gold quality
visceral pleura	UBERON:0002401	98.49	gold quality
medial globus pallidus	UBERON:0002477	98.40	gold quality
globus pallidus	UBERON:0001875	98.39	gold quality
cranial nerve II	UBERON:0000941	98.38	gold quality
cardia of stomach	UBERON:0001162	98.26	gold quality
secondary oocyte	CL:0000655	98.25	gold quality
pylorus	UBERON:0001166	98.23	gold quality
tendon of biceps brachii	UBERON:0008188	98.17	gold quality
pleura	UBERON:0000977	98.16	gold quality
lateral globus pallidus	UBERON:0002476	98.16	gold quality
parietal pleura	UBERON:0002400	98.10	gold quality
olfactory bulb	UBERON:0002264	98.02	gold quality
medulla oblongata	UBERON:0001896	97.93	gold quality
mucosa of paranasal sinus	UBERON:0005030	97.92	gold quality
subthalamic nucleus	UBERON:0001906	97.88	gold quality
ventral tegmental area	UBERON:0002691	97.81	gold quality
cartilage tissue	UBERON:0002418	97.79	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.77	gold quality
bronchial epithelial cell	CL:0002328	97.72	gold quality
oocyte	CL:0000023	97.65	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	7041.67
E-MTAB-11268	yes	3664.13
E-MTAB-6701	yes	48.00
E-HCAD-11	yes	6.66
E-MTAB-10042	yes	4.39
E-GEOD-124858	no	1094.43
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

161 targets.

Target	Regulation
ABCC1	Activation
ACTA2	Repression
ADAM19	Activation
AHSP	Activation
AKT1
ASCL1	Repression
ATM	Activation
ATP5PD	Repression
BCL2	Activation
BIRC5	Repression
BMP10	Activation
BMP2
BNIP3	Activation
CASP3	Activation
CCND3
CD40
CD8A	Repression
CDH2	Activation
CDH5	Repression
CDK6
CDKN1A	Activation
CDKN1B	Activation
CEBPA	Repression
CEBPZ	Repression
CHST12	Repression
CLCN1	Repression
CR2	Unknown
CRTC1
CSF1	Repression
CYP26A1	Unknown

JASPAR motifs

Motif	Name	Family
MA1116.1	RBPJ	CSL-related factors
MA1116.2	RBPJ	CSL-related factors

JASPAR matrix evidence (PMIDs): PMID:23651858

Upstream regulators (CollecTRI, top): AP1, CEBPB, GATA5, RBPJ, SOX2

miRNA regulators (miRDB)

275 targeting RBPJ, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
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

Literature-anchored findings (GeneRIF, showing 40)

• SHARP is a novel component of the HDAC corepressor complex, recruited by RBP-Jkappa to repress transcription of target genes in the absence of activated Notch. (PMID:12374742)
• RBP-J kappa-mediated repression is therefore not essential for establishment of latent KHSV infection, but the RTA-mediated redirection of RBP-J kappa activity from repression to activation is critical for lytic viral replication. (PMID:12832621)
• Ku antigen interacts with RBP-Jkappa and NF-kappaB p50 may act as a positive regulator of p50 expression in gastric cancer AGS cells. (PMID:14570916)
• C promoter-binding factor 1 binding is required for Notch-1-mediated repression of activator protein-1 (PMID:14645224)
• RBP-Jkappa activated a full transcriptional response but only demonstrated partial antiapoptotic activity (PMID:14701863)
• The ankyrin repeats were also the only domain required for up-regulation of RBP-Jkappa-dependent gene expression (PMID:15187023)
• regulates Kaposi’s sarcoma-associated herpesvirus (KSHV) K14/vGPCR transcripts; this suggests the possibility that other modulators of Notch signaling might be able to induce expression of this RNA outside the context of lytic KSHV replication. (PMID:15194757)
• 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)
• a corepressor complex containing CtIP/CtBP facilitates RBP-Jkappa/SHARP-mediated repression of Notch target genes (PMID:16287852)
• P48 interacts with the RBP-L and RBP-J subunits primarily through two short conserved tryptophan-containing motifs, similar to the motif of the Notch intracellular domain (NotchIC) that interacts with RBP-J. (PMID:16354684)
• c-Myc can cooperate with E6/E7 in epithelial transformation and can substitute for CBF1-dependent signals generated by Notch1. (PMID:16378632)
• Notch/Rbp-j signaling prevents premature differentiation of pancreatic progenitor cells into endocrine and ductal cells during early development of the transgenic pancreas. (PMID:16399505)
• findings show that induction of FcRH5 by Epstein-Barr virus nuclear antigen 2 is strictly CBF1 dependent (PMID:16439682)
• Results report the crystal structure of a Notch transcriptional activation complex containing the ankyrin domain of human Notch1, the transcription factor CSL on cognate DNA, and a polypeptide from the coactivator Mastermind-like-1 (MAML-1). (PMID:16530044)
• EBNA2 trans-activates bfl-1, which requires CBF1 (or RBP-J kappa). (PMID:16873269)
• RTA activates the Kaposi’s sarcoma-associated herpesvirus K8 promoter through an indirect binding mechanism, i.e. being recruited to the K8 promoter through interaction with RBP-Jkappa bound to an RBP-Jkappa motif in the promoter (PMID:17055026)
• These results support an emerging molecular mechanism for the displacement of co-repressors from DNA-bound CSL by intracellular domain of the Notch receptor . (PMID:17070841)
• The phosphatase and tensin homolog (PTEN) gene is a direct target of Notch-1 signal transduction, through binding of the Notch-activated transcription factor CBF-1 to the PTEN minimal promoter. (PMID:17245125)
• A number of Notch-regulated targets are characterized by paired CSL-binding sites in a head-to-head arrangement; cooperative formation of dimeric Notch transcription complexes on promoters with paired sites is required to activate transcription (PMID:17284587)
• Transcription factor Ying Yang 1 (YY1) indirectly regulates the C promoter-binding factor 1 (CBF1)-dependent Notch1 signaling via direct interaction with the Notch1 receptor. (PMID:17434929)
• an important relationship exists between zinc and the Notch1 signaling pathway, and that this relationship is intimately involved with the cytoplasmic retention of Notch and RBP-Jk (PMID:17513037)
• The incorporation of RBP-J kappa into CCAAT-enhancer-binding protein (CEBP) zeta complexes in human hepatoma Hep3B cells is solely to support the binding of CEBP zeta to the CEBP site. (PMID:17513780)
• the RBP-Jkappa-associated domain of Notch increases the effective concentration of the ankyrin domain for its binding site on CSL, enabling docking of the ankyrin domain and subsequent recruitment of the Mastermind-like coactivator. (PMID:18155729)
• Present a novel mechanism by which a balance between Notch-1/-2/-4 signaling, via CBF-1, and HRT-1/-2 activity determines the expression of smooth muscle differentiation markers including actin. (PMID:18239137)
• ETO is part of the endogenous RBP-Jkappa-containing corepressor complex (PMID:18332109)
• In gliomas, the TNC gene is transactivated by Notch2 in an RBPJk-dependent manner mediated by an RBPJk binding element in the TNC promoter. (PMID:19147558)
• EBNA3C regulation of transcription through RBP-Jkappa is critical to maintaining lymphoblastoid cell growth (PMID:19237563)
• Studies indicate that the mechanisms that lead to Notch activity in the receiving cell include the cleavage of Notch at the cell membrane and the assembly of a nuclear complex with the transcription factors CSL. (PMID:19247952)
• Both CBF1 and C/EBP-beta bind the CR2 promoter in B cells raising the possibility that these factors facilitate or respond to alterations in chromatin structure to control the timing and/or level of CR2 transcription. (PMID:19487031)
• The authors confirmed that EBNA3C upregulates TCL1 and discovered that EBNA3C upregulates TCL1 through RBP-Jkappa, indicating a central role for EBNA3C interaction with RBP-Jkappa in mediating cell gene transcription. (PMID:19776126)
• Data support a model in which Notch-1 can activate the transcription of ERalpha-target genes via IKKalpha-dependent cooperative chromatin recruitment of Notch-CSL-MAML1 and ERalpha, which promotes the recruitment of p300. (PMID:19838210)
• Inhibition of methylation in EBV-infected cells results in reduced expression of the EBNA2-regulated viral gene LMP1, evidencing that methylation is a prerequisite for DNA-binding by EBNA2 via association with the transcription factor RBPJkappa. (PMID:19969318)
• The interactions of RBPJ with ORF47 and ORF50 human herpesvirus 8 proteins in transactivation are reported. (PMID:20006367)
• mechanism by which the PhiW PhiP motif of RAM and EBNA2 compete with one another for binding at the hydrophobic pocket of the beta-trefoil domain (BTD) of CSL using overlapping but specific interactions that are unique to each BTD ligand. (PMID:20028974)
• Notch target gene activator RBP-J kappa transgene plays no role in Notch target gene repression in Ikaros double-positive thymocytes during leukemia development. (PMID:20511547)
• These results indicate that EBNA3 proteins interact with multiple RBP/CSL domains, but only N-terminal domain interactions are required for lymphoblastoid cell line growth. (PMID:21440926)
• The RBP-Jkappa binding site within the KSHV LANA promoter is crucial for HHV8 latency during early primary infection. (PMID:21507979)
• data strongly support a model in which EBNA2 association with NCoR-deficient RBPJ enhances transcription and EBNALP dismisses NCoR and RBPJ repressive complexes from enhancers (PMID:21518914)
• Collectively, our results demonstrate that APP intracellular domain functions as a negative regulator in Notch1 signaling through the promotion of Notch1 and RBP-Jk protein degradation (PMID:21558417)
• there is a conserved network of cis-regulatory factors that interacts with Notch1 to regulate gene expression in TLL cells, as well as unique classes of divergent RBPJ-only sites that also likely regulate transcription (PMID:21737748)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rbpja	ENSDARG00000003398
danio_rerio	rbpjb	ENSDARG00000052091
mus_musculus	Rbpj	ENSMUSG00000039191
rattus_norvegicus	Rbpj	ENSRNOG00000046327
drosophila_melanogaster	Su(H)	FBGN0004837

Paralogs (1): RBPJL (ENSG00000124232)

Protein

Protein identifiers

Recombining binding protein suppressor of hairless — Q06330 (reviewed: Q06330)

Alternative names: CBF-1, J kappa-recombination signal-binding protein, RBP-J kappa, Renal carcinoma antigen NY-REN-30

All UniProt accessions (28): A0A7P0T7Z3, A0A7P0T806, A0A7P0T821, A0A7P0T848, A0A7P0T947, A0A7P0T964, A0A7P0T9W9, A0A7P0T9Y9, A0A7P0TA33, A0A7P0TBJ4, A0A7P0Z4N7, D6R927, D6R946, D6R9K5, D6R9X3, D6RA45, D6RAT2, D6RB37, D6RBQ8, D6RCM1, D6RE93, Q06330, D6REC2, D6REP3, D6RF98, D6RIV8, D6RIZ8, H0Y8R3

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator that plays a central role in Notch signaling, a signaling pathway involved in cell-cell communication that regulates a broad spectrum of cell-fate determinations. Acts as a transcriptional repressor when it is not associated with Notch proteins. When associated with some NICD product of Notch proteins (Notch intracellular domain), it acts as a transcriptional activator that activates transcription of Notch target genes. Probably represses or activates transcription via the recruitment of chromatin remodeling complexes containing histone deacetylase or histone acetylase proteins, respectively. Specifically binds to the immunoglobulin kappa-type J segment recombination signal sequence. Binds specifically to methylated DNA. Binds to the oxygen responsive element of COX4I2 and activates its transcription under hypoxia conditions (4% oxygen). Negatively regulates the phagocyte oxidative burst in response to bacterial infection by repressing transcription of NADPH oxidase subunits.

Subunit / interactions. Interacts with activated NOTCH1, NOTCH2 or NOTCH3. Interacts with MINT/SHARP. This interaction may mediate the recruitment of large corepressor complexes containing proteins such as HDAC1, HDAC2, NCOR2, SAP30, FHL1/KYOT2 and CIRSR. Interacts with EP300, MAML1 and PTF1A. Interacts with RITA1/C12orf52, leading to nuclear export, prevent the interaction between RBPJ and NICD product and subsequent down-regulation of the Notch signaling pathway. Interacts with SNW1. Interacts with CHCHD2 and CXXC5. Interacts with BEND6 (via BEN domain). Interacts with NKAPL. Interacts with ZMIZ1. Interacts with RBM15. Interacts with L3MBTL3 and KDM1A; the interaction with KDM1A is weaker in the absence of L3MBTL3 and the interaction with L3MBTL3 is impaired by Notch-derived peptide containing the intracellular domain (NICD). (Microbial infection) Interacts with EBV EBNA2. Interacts with EBV EBNA3. Interacts with EBV EBNA4. Interacts with EBV EBNA6 (via N-terminus).

Subcellular location. Nucleus. Cytoplasm.

Disease relevance. Adams-Oliver syndrome 3 (AOS3) [MIM:614814] An autosomal dominant 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. AOS3 patients manifest characteristic vertex scalp defects and terminal limb defects, but without congenital heart defects, other associated defects, or immune defects. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Su(H) family.

Isoforms (7)

UniProt ID	Names	Canonical?
Q06330-1	APCR-2	yes
Q06330-2	APCR-1
Q06330-3	APCR-3
Q06330-4	4
Q06330-5	5
Q06330-6	6
Q06330-7	7

RefSeq proteins (13): NP_001350506, NP_001361329, NP_001361330, NP_001361331, NP_001361332, NP_001366335, NP_001366336, NP_001366337, NP_001366338, NP_005340, NP_056958, NP_976028, NP_976029 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008967	p53-like_TF_DNA-bd_sf	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR014756	Ig_E-set	Homologous_superfamily
IPR015350	Beta-trefoil_DNA-bd_dom	Domain
IPR015351	RBP-J/Cbf11/Cbf12_DNA-bd	Domain
IPR036358	BTD_sf	Homologous_superfamily
IPR037095	RBP-J/Cbf11_DNA-bd_sf	Homologous_superfamily
IPR038007	RBP-Jkappa_IPT	Domain
IPR040159	CLS_fam	Family

Pfam: PF09270, PF09271, PF20144

UniProt features (75 total): strand 35, sequence variant 8, splice variant 7, sequence conflict 7, region of interest 5, helix 5, turn 3, compositionally biased region 2, chain 1, domain 1, modified residue 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2F8X	X-RAY DIFFRACTION	3.25
3NBN	X-RAY DIFFRACTION	3.45
6PY8	X-RAY DIFFRACTION	3.75
3V79	X-RAY DIFFRACTION	3.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q06330-F1	85.76	0.73

Functional residue map

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

Post-translational modifications (1): 175

Function

Pathways and Gene Ontology

Reactome pathways

32 pathways

ID	Pathway
R-HSA-1912408	Pre-NOTCH Transcription and Translation
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-2197563	NOTCH2 intracellular domain regulates transcription
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-350054	Notch-HLH transcription pathway
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-9824272	Somitogenesis
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)
R-HSA-1266738	Developmental Biology
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-186712	Regulation of beta-cell development
R-HSA-1912422	Pre-NOTCH Expression and Processing
R-HSA-1980143	Signaling by NOTCH1
R-HSA-1980145	Signaling by NOTCH2
R-HSA-212436	Generic Transcription Pathway
R-HSA-2644602	Signaling by NOTCH1 PEST Domain Mutants in Cancer
R-HSA-2644603	Signaling by NOTCH1 in Cancer
R-HSA-2894858	Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878159	Transcriptional regulation by RUNX3
R-HSA-9012852	Signaling by NOTCH3

MSigDB gene sets: 836 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, REACTOME_SIGNALING_BY_NOTCH, E2F_Q4_01, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, GOBP_LUNG_EPITHELIUM_DEVELOPMENT, GOBP_DENDRITIC_CELL_DIFFERENTIATION, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY

GO Biological Process (69): negative regulation of transcription by RNA polymerase II (GO:0000122), angiogenesis (GO:0001525), somitogenesis (GO:0001756), epithelial to mesenchymal transition (GO:0001837), blood vessel remodeling (GO:0001974), inflammatory response to antigenic stimulus (GO:0002437), secondary heart field specification (GO:0003139), outflow tract morphogenesis (GO:0003151), endocardium morphogenesis (GO:0003160), aortic valve development (GO:0003176), pulmonary valve development (GO:0003177), epithelial to mesenchymal transition involved in endocardial cushion formation (GO:0003198), cardiac left ventricle morphogenesis (GO:0003214), ventricular trabecula myocardium morphogenesis (GO:0003222), regulation of transcription by RNA polymerase II (GO:0006357), humoral immune response (GO:0006959), Notch signaling pathway (GO:0007219), positive regulation of transcription of Notch receptor target (GO:0007221), heart development (GO:0007507), auditory receptor cell fate commitment (GO:0009912), epidermal cell fate specification (GO:0009957), positive regulation of gene expression (GO:0010628), pituitary gland development (GO:0021983), B cell differentiation (GO:0030183), keratinocyte differentiation (GO:0030216), negative regulation of ossification (GO:0030279), positive regulation of BMP signaling pathway (GO:0030513), somatic stem cell population maintenance (GO:0035019), dorsal aorta morphogenesis (GO:0035912), atrioventricular canal development (GO:0036302), defense response to bacterium (GO:0042742), myeloid dendritic cell differentiation (GO:0043011), regulation of generation of precursor metabolites and energy (GO:0043467), negative regulation of cell differentiation (GO:0045596), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of timing of cell differentiation (GO:0048505), sebaceous gland development (GO:0048733), hair follicle maturation (GO:0048820), epithelial cell proliferation (GO:0050673)

GO Molecular Function (10): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), sequence-specific DNA binding (GO:0043565), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), DNA-binding transcription factor binding (GO:0140297), protein binding (GO:0005515)

GO Cellular Component (8): chromatin (GO:0000785), MAML1-RBP-Jkappa- ICN1 complex (GO:0002193), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), transcription repressor complex (GO:0017053), transcription regulator complex (GO:0005667)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Signaling by NOTCH	2
Pre-NOTCH Expression and Processing	1
Regulation of beta-cell development	1
Signaling by NOTCH1	1
Signaling by NOTCH2	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
Generic Transcription Pathway	1
Transcriptional regulation by RUNX3	1
Signaling by NOTCH3	1
Signaling by NOTCH4	1
Gastrulation	1
Formation of paraxial mesoderm	1
Differentiation of T cells	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
anatomical structure formation involved in morphogenesis	2
immune response	2
anatomical structure morphogenesis	2
semi-lunar valve development	2
regulation of DNA-templated transcription	2
positive regulation of transcription by RNA polymerase II	2
binding	2
protein-containing complex	2
nuclear lumen	2
negative regulation of DNA-templated transcription	1
blood vessel morphogenesis	1
anterior/posterior pattern specification	1
segmentation	1
chordate embryonic development	1
somite development	1
mesenchymal cell differentiation	1
tissue remodeling	1
inflammatory response	1
heart field specification	1
heart morphogenesis	1
endocardium development	1
endocardial cushion formation	1
cardiac epithelial to mesenchymal transition	1
cardiac ventricle morphogenesis	1
ventricular cardiac muscle tissue morphogenesis	1
heart trabecula morphogenesis	1
cell surface receptor signaling pathway	1
Notch signaling pathway	1
animal organ development	1
circulatory system development	1
inner ear auditory receptor cell differentiation	1
inner ear receptor cell fate commitment	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1

Protein interactions and networks

STRING

3494 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RBPJ	MAML1	Q92585	999
RBPJ	NOTCH1	P46531	999
RBPJ	MAML2	Q8IZL2	999
RBPJ	MAML3	Q96JK9	999
RBPJ	PTF1A	Q7RTS3	983
RBPJ	GNLY	P09325	965
RBPJ	NCOR2	Q9Y618	959
RBPJ	CTNNB1	P35222	940
RBPJ	NOTCH2	Q04721	939
RBPJ	JAG1	P78504	917
RBPJ	NOTCH3	Q9UM47	917
RBPJ	NCOR1	O75376	915
RBPJ	KAT2B	Q92831	903
RBPJ	DLL1	O00548	898
RBPJ	NOTCH4	Q99466	876

IntAct

130 interactions, top by confidence:

A	B	Type	Score
MAML1	NOTCH1	psi-mi:“MI:0914”(association)	0.950
RBPJ	NOTCH1	psi-mi:“MI:0914”(association)	0.910
RBPJ	NOTCH1	psi-mi:“MI:0915”(physical association)	0.910
MED23	MED19	psi-mi:“MI:2364”(proximity)	0.770
RITA1	RBPJ	psi-mi:“MI:0915”(physical association)	0.730
RBPJ	RITA1	psi-mi:“MI:0407”(direct interaction)	0.730
RITA1	RBPJ	psi-mi:“MI:0407”(direct interaction)	0.730
RBPJ	RITA1	psi-mi:“MI:0915”(physical association)	0.730
RBPJ	RITA1	psi-mi:“MI:0403”(colocalization)	0.730
RBPJ	SPEN	psi-mi:“MI:0407”(direct interaction)	0.690
FBXO42	GSK3A	psi-mi:“MI:0914”(association)	0.660
RBPJ	EBNA3	psi-mi:“MI:0915”(physical association)	0.650
RBPJ	TP53	psi-mi:“MI:0915”(physical association)	0.650
RBPJ	TP53	psi-mi:“MI:0407”(direct interaction)	0.650
EBNA3	RBPJ	psi-mi:“MI:0915”(physical association)	0.650
KDM1A	RBPJ	psi-mi:“MI:0915”(physical association)	0.640
RBPJ	KDM1A	psi-mi:“MI:0915”(physical association)	0.640
RBPJ	ATXN1L	psi-mi:“MI:0914”(association)	0.640
RBPJ	ATXN1	psi-mi:“MI:0915”(physical association)	0.640
ATXN1L	RBPJ	psi-mi:“MI:0915”(physical association)	0.640

BioGRID (412): RBPJ (Reconstituted Complex), RBPJ (Two-hybrid), RBPJ (Affinity Capture-Western), NOTCH1 (Affinity Capture-Western), WDR70 (Affinity Capture-MS), SPEN (Affinity Capture-MS), NOTCH1 (Affinity Capture-MS), NOTCH2 (Affinity Capture-MS), NOTCH3 (Affinity Capture-MS), USP7 (Affinity Capture-MS), FBXO42 (Affinity Capture-MS), MAML1 (Affinity Capture-MS), ZNF589 (Affinity Capture-MS), DCAF16 (Affinity Capture-MS), ZNF268 (Affinity Capture-MS)

ESM2 similar proteins: A2VE39, A4IID4, A4QP78, A9X1A0, B0BNK8, B0KWC1, B1MTG7, B2KI64, B3EX61, B4UT09, D2HRF1, D3Z5S8, F7E7M3, F8VPU6, O00763, O02019, O02810, O08561, O35099, P31266, Q06330, Q08BW6, Q29RH2, Q2M146, Q3SZ41, Q4R8X4, Q5R981, Q5RFK6, Q5RHQ8, Q5SSF7, Q5U4W6, Q5VWP2, Q5XIV0, Q5ZJT0, Q5ZL95, Q6GN16, Q6PCM2, Q7Z5Y7, Q7ZUP1, Q8BKC8

Diamond homologs: O02019, O08674, O76808, P28159, P31266, Q06330, Q3SZ41, Q5RFK6, Q91880, Q9UBG7, V6CLJ5, O74954, Q9Y1T5

SIGNOR signaling

27 interactions.

A	Effect	B	Mechanism
RBPJ	“up-regulates quantity by expression”	CDKN1A	“transcriptional regulation”
HES1	down-regulates	RBPJ	binding
HEY1	down-regulates	RBPJ	binding
MAPK8IP1	down-regulates	RBPJ	binding
RITA1	down-regulates	RBPJ	binding
FOXC1	up-regulates	RBPJ	binding
RBPJ	up-regulates	MAML2	binding
RBPJ	up-regulates	MAML3	binding
NOTCH1	up-regulates	RBPJ	binding
RBPJ	up-regulates	PAX7	binding
RBPJ	“form complex”	RBPJ/NOTCH	binding
MAPK14	“down-regulates quantity by destabilization”	RBPJ	phosphorylation
FHL1	down-regulates	RBPJ	binding
RBPJ	“down-regulates quantity by repression”	NFKB2	“transcriptional regulation”
RBPJ	up-regulates	GTF2A2	binding
RBPJ	up-regulates	CIR1	binding
RBPJ	“up-regulates quantity by expression”	HES1	binding
MAML1	up-regulates	RBPJ	binding
NOTCH3	up-regulates	RBPJ	binding
SPEN	down-regulates	RBPJ	binding
RBPJ	up-regulates	DUSP1	binding
RBPJ	“up-regulates quantity”	HES1	“transcriptional regulation”
DVL2	“down-regulates activity”	RBPJ	binding
RBPJ	“down-regulates quantity by repression”	NOTCH	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 86 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
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	5	63.7×	3e-07
Notch-HLH transcription pathway	7	51.0×	1e-08
NOTCH4 Intracellular Domain Regulates Transcription	5	51.0×	1e-06
Signaling by NOTCH1 PEST Domain Mutants in Cancer	6	43.7×	2e-07
Signaling by NOTCH1 in Cancer	6	43.7×	2e-07
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	6	43.7×	2e-07
NOTCH3 Intracellular Domain Regulates Transcription	5	39.2×	4e-06
Signaling by NOTCH1	6	38.2×	3e-07

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of transcription initiation by RNA polymerase II	5	19.4×	9e-04
Notch signaling pathway	6	12.1×	1e-03
transcription by RNA polymerase II	7	7.0×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	4
Uncertain significance	76
Likely benign	62
Benign	47

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
37054	NM_015874.6(RBPJ):c.466A>G (p.Lys156Glu)	Pathogenic
1803755	NM_015874.6(RBPJ):c.155G>C (p.Arg52Thr)	Likely pathogenic
523586	NM_015874.6(RBPJ):c.154A>G (p.Arg52Gly)	Likely pathogenic
523587	NM_015874.6(RBPJ):c.157T>G (p.Phe53Val)	Likely pathogenic
523588	NM_015874.6(RBPJ):c.957C>A (p.Ser319Arg)	Likely pathogenic

SpliceAI

3133 predictions. Top by Δscore:

Variant	Effect	Δscore
4:26319854:A:T	donor_gain	1.0000
4:26322634:T:G	donor_gain	1.0000
4:26362444:A:G	acceptor_gain	1.0000
4:26386348:TCCAG:T	acceptor_loss	1.0000
4:26386349:CCAGG:C	acceptor_loss	1.0000
4:26386350:CAGGA:C	acceptor_loss	1.0000
4:26386351:A:AG	acceptor_gain	1.0000
4:26386351:AG:A	acceptor_gain	1.0000
4:26386352:G:GA	acceptor_gain	1.0000
4:26386352:GG:G	acceptor_gain	1.0000
4:26386352:GGA:G	acceptor_gain	1.0000
4:26386352:GGAA:G	acceptor_gain	1.0000
4:26386352:GGAAA:G	acceptor_gain	1.0000
4:26386388:CTAG:C	donor_gain	1.0000
4:26386389:TAG:T	donor_gain	1.0000
4:26386390:AG:A	donor_gain	1.0000
4:26386391:GG:G	donor_gain	1.0000
4:26386392:G:GG	donor_gain	1.0000
4:26386392:GT:G	donor_loss	1.0000
4:26406169:TTTTA:T	acceptor_loss	1.0000
4:26406170:TTTA:T	acceptor_loss	1.0000
4:26406171:TTA:T	acceptor_loss	1.0000
4:26406172:TA:T	acceptor_loss	1.0000
4:26406173:A:AC	acceptor_loss	1.0000
4:26406173:A:AG	acceptor_gain	1.0000
4:26406173:AG:A	acceptor_gain	1.0000
4:26406174:G:GG	acceptor_gain	1.0000
4:26406174:GG:G	acceptor_gain	1.0000
4:26406174:GGGA:G	acceptor_gain	1.0000
4:26406174:GGGAA:G	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000028229 (4:26294604 G>A,T), RS1000028510 (4:26428913 C>A,T), RS1000039268 (4:26373146 T>C), RS1000047655 (4:26126316 C>G,T), RS10000489 (4:26115139 A>G), RS1000062373 (4:26302494 C>T), RS1000064839 (4:26330652 T>TC), RS1000068664 (4:26199497 G>A), RS10000787 (4:26173138 C>G,T), RS10000798 (4:26173177 C>T), RS1000080086 (4:26211691 G>A,C), RS10000896 (4:26173299 C>A), RS1000097866 (4:26348924 C>T), RS10001040 (4:26143156 G>T), RS1000113530 (4:26113219 TG>T,TGG)

Disease associations

OMIM: gene MIM:147183 | disease phenotypes: MIM:614814, MIM:233650, MIM:125853

GenCC curated gene-disease

Disease	Classification	Inheritance
Adams-Oliver syndrome 3	Strong	Autosomal dominant
Adams-Oliver syndrome	Supportive	Autosomal dominant

Mondo (4): Adams-Oliver syndrome 3 (MONDO:0013895), combined immunodeficiency with skin granulomas (MONDO:0009306), type 2 diabetes mellitus (MONDO:0005148), Adams-Oliver syndrome (MONDO:0007034)

Orphanet (2): Adams-Oliver syndrome (Orphanet:974), Combined immunodeficiency with granulomatosis (Orphanet:157949)

HPO phenotypes

57 total (30 of 57 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000486	Strabismus
HP:0000518	Cataract
HP:0000568	Microphthalmia
HP:0000965	Cutis marmorata
HP:0001057	Aplasia cutis congenita
HP:0001156	Brachydactyly
HP:0001171	Split hand
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001256	Mild intellectual disability
HP:0001269	Hemiparesis
HP:0001276	Hypertonia
HP:0001362	Calvarial skull defect
HP:0001394	Cirrhosis
HP:0001409	Portal hypertension
HP:0001508	Failure to thrive
HP:0001541	Ascites
HP:0001596	Alopecia
HP:0001622	Premature birth
HP:0001636	Tetralogy of Fallot
HP:0001641	Abnormal pulmonary valve morphology
HP:0001804	Hypoplastic fingernail
HP:0001817	Absent fingernail
HP:0001873	Thrombocytopenia
HP:0001882	Decreased total leukocyte count
HP:0001883	Talipes
HP:0002040	Esophageal varix

GWAS associations

37 associations (top):

Study	Trait	p-value
GCST002323_3	Rheumatoid arthritis	4.000000e-07
GCST005568_32	Rheumatoid arthritis (ACPA-positive)	6.000000e-13
GCST005569_30	Rheumatoid arthritis	4.000000e-10
GCST005569_7	Rheumatoid arthritis	6.000000e-13
GCST006048_49	Rheumatoid arthritis (ACPA-positive)	8.000000e-14
GCST006979_428	Heel bone mineral density	5.000000e-10
GCST007932_37	Medication use (thyroid preparations)	2.000000e-16
GCST009873_35	Autoimmune traits (pleiotropy)	3.000000e-12
GCST010173_60	Triglyceride levels	1.000000e-16
GCST010241_28	Apolipoprotein A1 levels	6.000000e-17
GCST010243_142	Apolipoprotein B levels	8.000000e-09
GCST010244_363	Triglyceride levels	5.000000e-08
GCST011939_10	Takayasu arteritis	6.000000e-06
GCST011939_9	Takayasu arteritis	7.000000e-06
GCST012228_70	Waist-hip index	4.000000e-08
GCST012228_71	Waist-hip index	3.000000e-08
GCST012228_72	Waist-hip index	8.000000e-12
GCST012228_73	Waist-hip index	3.000000e-08
GCST012228_74	Waist-hip index	5.000000e-10
GCST012230_271	Waist-to-hip ratio adjusted for BMI	3.000000e-08
GCST012230_272	Waist-to-hip ratio adjusted for BMI	1.000000e-08
GCST012230_273	Waist-to-hip ratio adjusted for BMI	1.000000e-11
GCST012230_274	Waist-to-hip ratio adjusted for BMI	7.000000e-10
GCST012231_218	A body shape index	2.000000e-08
GCST90000025_263	Appendicular lean mass	3.000000e-14
GCST90002394_273	Monocyte percentage of white cells	1.000000e-10
GCST90020024_697	A body shape index	3.000000e-08
GCST90020024_698	A body shape index	1.000000e-11
GCST90020024_699	A body shape index	2.000000e-08
GCST90020025_310	Waist-to-hip ratio adjusted for BMI	7.000000e-09

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0009933	Thyroid preparation use measurement
EFO:0004530	triglyceride measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004615	apolipoprotein B measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0007789	BMI-adjusted waist circumference
EFO:0004980	appendicular lean mass
EFO:0007989	monocyte percentage of leukocytes

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300
C538225	Adams Oliver syndrome (supp.)
C567115	Combined Cellular And Humoral Immune Defects With Granulomas (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105709 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

29 measured of 29 human assays (29 total across all organisms); most potent 29 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(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)-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)-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)-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)-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)-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)-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)-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-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)-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)-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)-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)-2-(4,4-difluorocyclohexyl)-N’-[(3S)-9-methoxy-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	7 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-N’-[(3S)-9-aminooxy-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-2-(3-fluoropropyl)-3-(3,3,3-trifluoropropyl)butanediamide	IC50	7 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-2-(3,3-difluorobutyl)-N’-[(3S)-9-methoxy-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	7.5 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-fluoropropyl)-3-(3,3,3-trifluoropropyl)butanediamide	IC50	10.8 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-[4-(trifluoromethyl)cyclohexyl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	11.9 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-3-(2-methylpropyl)-N’-[(3S)-2-oxo-5-phenyl-1-propyl-3H-1,4-benzodiazepin-3-yl]-2-prop-2-enylbutanediamide	IC50	12.3 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-2-(3,3-difluorocyclobutyl)-N’-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]-3-(3,3,3-trifluoropropyl)butanediamide	IC50	14 nM	US-9427442: Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds
(2S,3R)-N’-[(3S)-7-chloro-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-3-(2-methylpropyl)-2-prop-2-enylbutanediamide	IC50	42.4 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof
(2S,3R)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-3-(2-methylpropyl)-2-propylbutanediamide	IC50	64.1 nM	US-9273014: Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof

ChEMBL bioactivities

33 potent at pChembl≥5 of 33 total, top 29 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.85	IC50	1.4	nM	CHEMBL4111071
8.68	IC50	2.1	nM	CHEMBL4112855
8.66	IC50	2.2	nM	CHEMBL4114579
8.62	IC50	2.4	nM	CHEMBL4111904
8.62	IC50	2.4	nM	CHEMBL4114126
8.62	IC50	2.4	nM	CHEMBL3921166
8.49	IC50	3.2	nM	CHEMBL4107767
8.49	IC50	3.2	nM	CHEMBL3896414
8.42	IC50	3.8	nM	CHEMBL4107070
8.40	IC50	4	nM	CHEMBL4112577
8.37	IC50	4.3	nM	CHEMBL4106629
8.36	IC50	4.4	nM	CHEMBL4109925
8.27	IC50	5.4	nM	CHEMBL3935675
8.22	IC50	6	nM	CHEMBL4115546
8.14	IC50	7.3	nM	CHEMBL4112450
8.05	IC50	8.9	nM	CHEMBL4108092
8.03	IC50	9.3	nM	CHEMBL4108896
7.97	IC50	10.8	nM	CHEMBL4111709
7.96	IC50	11	nM	CHEMBL3958560
7.90	IC50	12.5	nM	CHEMBL3957276
7.87	IC50	13.5	nM	CHEMBL3974604
7.86	IC50	13.8	nM	CHEMBL3890931
7.81	IC50	15.4	nM	CHEMBL3975558
7.78	IC50	16.5	nM	CHEMBL3956533
7.72	IC50	18.9	nM	CHEMBL4113103
7.70	IC50	20.1	nM	CHEMBL4107530
7.67	IC50	21.2	nM	CHEMBL4112536
7.32	IC50	48.3	nM	CHEMBL429441
7.13	IC50	74.5	nM	CHEMBL3945182

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	4
cobaltous chloride	increases expression, decreases reaction	2
nickel sulfate	decreases expression	2
Irinotecan	decreases expression, affects cotreatment	2
Arsenic	affects methylation, increases methylation	2
Hydrogen Peroxide	affects expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
N-((3,5-difluorophenyl)acetyl)alanyl-2-phenylglycine-1,1-dimethylethyl ester	decreases expression	1
dicrotophos	decreases expression	1
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
HT-2 toxin	increases expression	1
arsenite	increases methylation	1
zinc chloride	decreases reaction, increases expression	1
sodium arsenite	affects expression	1
butyraldehyde	decreases expression	1
acetylleucyl-leucyl-norleucinal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
lactacystin	increases expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression, decreases reaction, affects reaction, affects response to substance, decreases expression	1
triptonide	decreases expression	1
CGP 52608	affects binding, increases reaction	1
SB 203580	affects reaction, affects response to substance, decreases expression	1
N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester	decreases expression, decreases reaction, increases expression	1
enzalutamide	affects expression	1
jinfukang	decreases expression	1
NSC668394	decreases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3888078	Binding	Transactivation Assay: The Notch-CBF1 (C-promoter binding factor I) cell based transactivation assay is based on the ability of the released Notch intracellular domain fragments (NICDs) to function as transcription factors in conjunction wi	Bis(fluoroalkyl)-1,4-benzodiazepinone compounds and prodrugs thereof

Cellosaurus cell lines

12 cell lines: 8 cancer cell line, 3 embryonic stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A5T8	SEES3-1V human RBPJ, clone1	Embryonic stem cell	Male
CVCL_A5T9	SEES3-1V human RBPJ, clone2	Embryonic stem cell	Male
CVCL_A5U0	SEES3-1V human RBPJ, clone3	Embryonic stem cell	Male
CVCL_D7ZA	Ubigene A-549 RBPJ KO	Cancer cell line	Male
CVCL_D8UH	Ubigene HCT 116 RBPJ KO	Cancer cell line	Male
CVCL_D9QD	Ubigene HEK293 RBPJ KO	Transformed cell line	Female
CVCL_E0MM	Ubigene HeLa RBPJ KO	Cancer cell line	Female
CVCL_E5V5	DG-75 CBF1 KO clone SM166C52	Cancer cell line	Male
CVCL_E5V6	DG-75 CBF1 KO clone SM224.9	Cancer cell line	Male
CVCL_E5V7	DG-75 CBF1 KO clone SM223E3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00006163	PHASE4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	PHASE4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	PHASE4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	PHASE4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	PHASE4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	PHASE4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	PHASE4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	PHASE4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	PHASE4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	PHASE4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	PHASE4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	PHASE4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	PHASE4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	PHASE4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	PHASE4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	PHASE4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	PHASE4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	PHASE4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	PHASE4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	PHASE4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	PHASE4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	PHASE4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	PHASE4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	PHASE4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	PHASE4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	PHASE4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	PHASE4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	PHASE4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	PHASE4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	PHASE4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	PHASE4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	PHASE4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	PHASE4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	PHASE4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes
NCT00240422	PHASE4	COMPLETED	Trial to Compare the Effects of Either Telmisartan (40-80 mg PO Once Daily) or Ramipril (5-10 mg PO Once Daily) on Renal Endothelial Dysfunction in Hypertensive Patients With Type 2 Diabetes
NCT00241085	PHASE4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus