ERBB3

Summary

ERBB3 (erb-b2 receptor tyrosine kinase 3, HGNC:3431) is a protein-coding gene on chromosome 12q13.2, encoding Receptor tyrosine-protein kinase erbB-3 (P21860). Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins. In precision oncology, ERBB2 Mutation OR ERBB3 Mutation confers sensitivity to Trastuzumab + Pertuzumab in Colorectal Cancer (CIViC Level B); 17 further curated variant–drug associations are listed below.

This gene encodes a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. This membrane-bound protein has a neuregulin binding domain but not an active kinase domain. It therefore can bind this ligand but not convey the signal into the cell through protein phosphorylation. However, it does form heterodimers with other EGF receptor family members which do have kinase activity. Heterodimerization leads to the activation of pathways which lead to cell proliferation or differentiation. Amplification of this gene and/or overexpression of its protein have been reported in numerous cancers, including prostate, bladder, and breast tumors. Alternate transcriptional splice variants encoding different isoforms have been characterized. One isoform lacks the intermembrane region and is secreted outside the cell. This form acts to modulate the activity of the membrane-bound form. Additional splice variants have also been reported, but they have not been thoroughly characterized.

Source: NCBI Gene 2065 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lethal congenital contracture syndrome 2 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 28
• Clinical variants (ClinVar): 247 total — 7 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 59
• Druggable target: yes — 23 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 18 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 11 cancer types
• MANE Select transcript: NM_001982

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3431
Approved symbol	ERBB3
Name	erb-b2 receptor tyrosine kinase 3
Location	12q13.2
Locus type	gene with protein product
Status	Approved
Aliases	HER3
Ensembl gene	ENSG00000065361
Ensembl biotype	protein_coding
OMIM	190151
Entrez	2065

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 16 protein_coding, 16 retained_intron, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000267101, ENST00000411731, ENST00000415288, ENST00000546748, ENST00000546884, ENST00000548709, ENST00000549061, ENST00000549205, ENST00000549282, ENST00000549472, ENST00000549644, ENST00000549672, ENST00000549832, ENST00000550070, ENST00000550828, ENST00000550869, ENST00000551085, ENST00000551176, ENST00000551242, ENST00000552691, ENST00000553131, ENST00000643266, ENST00000643518, ENST00000682431, ENST00000682512, ENST00000682873, ENST00000683018, ENST00000683059, ENST00000683142, ENST00000683164, ENST00000683653, ENST00000684500, ENST00000684766, ENST00000878113, ENST00000878114, ENST00000878115, ENST00000926495

RefSeq mRNA: 2 — MANE Select: NM_001982 NM_001005915, NM_001982

CCDS: CCDS31833, CCDS44918

Canonical transcript exons

ENST00000267101 — 28 exons

Exon	Start	End
ENSE00001059664	56092747	56092820
ENSE00001143833	56098759	56098905
ENSE00001143926	56093345	56093550
ENSE00001143935	56092986	56093076
ENSE00001607896	56086531	56086656
ENSE00001696674	56087795	56087913
ENSE00001713759	56087577	56087642
ENSE00001784438	56088021	56088162
ENSE00002347570	56101529	56103505
ENSE00002427897	56080165	56080382
ENSE00003336426	56094402	56094556
ENSE00003384797	56094099	56094189
ENSE00003462599	56095257	56095310
ENSE00003469228	56088543	56088656
ENSE00003471260	56098500	56098575
ENSE00003491886	56096748	56096846
ENSE00003493556	56101061	56101361
ENSE00003532895	56097785	56097940
ENSE00003556105	56095665	56095806
ENSE00003556206	56084995	56085181
ENSE00003571409	56099648	56099745
ENSE00003586860	56088748	56088868
ENSE00003606070	56096503	56096622
ENSE00003647015	56083751	56083902
ENSE00003647790	56093764	56093896
ENSE00003660791	56097045	56097230
ENSE00003686253	56099838	56100029
ENSE00003689485	56100174	56100245

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 99.07.

FANTOM5 (CAGE): breadth broad, TPM avg 12.5090 / max 300.1572, expressed in 771 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126054	8.8360	703
126052	2.1530	553
126050	0.9881	412
126053	0.2865	184
126051	0.1502	81
126055	0.0953	43

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
trigeminal ganglion	UBERON:0001675	99.07	gold quality
jejunal mucosa	UBERON:0000399	98.89	gold quality
dorsal root ganglion	UBERON:0000044	98.82	gold quality
inferior vagus X ganglion	UBERON:0005363	98.52	gold quality
corpus callosum	UBERON:0002336	98.47	gold quality
colonic mucosa	UBERON:0000317	98.42	gold quality
ileal mucosa	UBERON:0000331	98.42	gold quality
lower esophagus mucosa	UBERON:0035834	98.30	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.29	gold quality
duodenum	UBERON:0002114	98.06	gold quality
lateral globus pallidus	UBERON:0002476	97.87	gold quality
tibial nerve	UBERON:0001323	97.77	gold quality
peripheral nervous system	UBERON:0000010	97.76	gold quality
nerve	UBERON:0001021	97.76	gold quality
pylorus	UBERON:0001166	97.62	gold quality
pharyngeal mucosa	UBERON:0000355	97.54	gold quality
bronchial epithelial cell	CL:0002328	97.44	gold quality
upper arm skin	UBERON:0004263	97.43	gold quality
upper leg skin	UBERON:0004262	97.38	gold quality
endometrium epithelium	UBERON:0004811	97.35	gold quality
subthalamic nucleus	UBERON:0001906	97.32	gold quality
saliva-secreting gland	UBERON:0001044	97.29	gold quality
minor salivary gland	UBERON:0001830	97.19	gold quality
parotid gland	UBERON:0001831	97.15	gold quality
sural nerve	UBERON:0015488	96.97	gold quality
mouth mucosa	UBERON:0003729	96.90	gold quality
skin of abdomen	UBERON:0001416	96.87	gold quality
esophagus mucosa	UBERON:0002469	96.77	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.73	gold quality
middle frontal gyrus	UBERON:0002702	96.69	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	323.78
E-MTAB-8410	yes	44.07
E-HCAD-11	yes	22.69
E-HCAD-9	yes	8.02
E-CURD-135	no	869.09
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
AR	Activation

Upstream regulators (CollecTRI, top): AR, FOXA1, GRHL2, NRG1, SOX10, TFAP2A, TFAP2C, TFAP2D, TWIST1, TWIST2, YBX1, ZNF217

miRNA regulators (miRDB)

154 targeting ERBB3, 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-548AW	99.99	72.57	3559
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777

Literature-anchored findings (GeneRIF, showing 40)

• AP-2gamma is important in the regulation of Erbb-3 expression in human mammary epithelial and lung fibroblast cells (PMID:11859873)
• Epidermal growth factor contains both positive and negative determinants for interaction with ErbB-2/ErbB-3 heterodimers (PMID:11914075)
• Role of the N-terminus of epidermal growth factor in binding studied by phage display. (PMID:12093292)
• structure reveals a contact between domains II and IV that constrains the relative orientations of ligand-binding domains (PMID:12154198)
• Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of this epidermal growth factor receptor family member (PMID:12411582)
• role of overexpression in lung cancer development in conjunction with erb-B-2 overexpression (PMID:12483526)
• the ErbB-3 affinity of a ligand determines whether it can form only ErbB-2/ErbB-3 complexes or also ErbB-3 homodimers. (PMID:12556529)
• Activation of ErbB3 pathway may contribute to the development of dedifferentiated carcinomas (PMID:12618754)
• Expression of epidermal growth factor receptor, erbB2, and erbB3, but not erbB4, was detected throughout the epidermis. Labeling for erbB2 and erbB3 accentuated in upper spinous layers (PMID:12768307)
• These results suggest that ErbB3 expression alone does not uniquely confer IFN-alpha growth responsiveness, but instead may amplify proliferation rates in MM cells that have acquired atypical expression of this receptor. (PMID:12789268)
• ErbB2/ErbB3 dimer functions as an oncogenic unit to drive breast tumor cell proliferation. (PMID:12853564)
• ERBB2 and ERBB3 expression is inhibited by quercetin, resulting in decreased autophosphorylation and cell growth (PMID:12888923)
• Overexpression of ErbB3 is associated with transitional cell carcinoma of the bladder (PMID:14614020)
• ErbB3 is involved in IFN-alpha-induced proliferation of myeloma cells. (PMID:14647450)
• heterodimer formation with heregulin regulates erbB2 receptor (PMID:14737100)
• This review summarizes evidence of defective expression of erbB3 in the prefrontal cortex of schizophrenic patients, implicating erbB3 involvement in the pathogenesis of schizophrenia. (PMID:15162166)
• ErbB3 is an obligate heterodimerization partner because of its inability to homodimerize. (PMID:15225657)
• before extracellular signal-regulated kinase activation and aquaporin synthesis, the membrane-bound prohormone neuregulin 1-beta is cleaved and binds to human epidermal growth factor receptor 3 (PMID:15498868)
• calculated binding free energies between the N-SH2 domain of PI-3 kinase and P-peptides generated by erbb3 showed excellent qualitative agreement with SPR data with a correlation coefficient of 0.91 (PMID:15520002)
• most of the ErbB3-ECD on the cell surface is apparently kept in an open conformation through oligomerization (PMID:15611073)
• ErbB3 proteins are promising targets for therapy, and siRNAs may be useful for this purpose. (PMID:15688028)
• Potential of anti-HER3 antibodies for the therapy of breast cancer and other malignancies characterized by overexpression of HER3. (PMID:15704104)
• Inhibition of HER2/HER3 signaling protects against pulmonary fibrosis and improves survival. (PMID:15731393)
• Transcriptional activity of eztrogen receptor beta was altered in a manner similar to ERalpha by activation of ErbB2/ErbB3. (PMID:15862947)
• Cell proliferation was increased when ErbB2 and ErbB3 were both overexpressed. (PMID:16199884)
• the most notable changes consisted in the overexpression of ErbB3 by Schwann cells of nerves from Charcot-Marie-tooth disease type 1A patients (PMID:16307437)
• ERBB3 is the pivotal element of the Erbb pathway promoting tumorigenesis by heterodimerization with NEU or EGFR, but the NEU/EGFR dimer does not appear to play a significant role in prostate cancer (PMID:16401639)
• HER2 overexpression was the best single predictive marker, but combinations of HER3, HER2 markers provided additional predictive information. (PMID:16622439)
• The high frequency of ErbB3 nuclear localization in hormone-refractory tissues indicates that ErbB3 warrants further study to understand its association with prostate cancer disease progression. (PMID:16675564)
• HER3 and HER4 has been related to a favourable prognosis in bladder cancer. (PMID:16685269)
• Muc4 potentiates neuregulin signaling by increasing the cell-surface populations of ErbB2 and ErbB3 (PMID:16690615)
• ErbB3 has six binding sites for PI3K. All three Y-E-Y motifs contain a binding site for PI3K at the first tyrosine residue. 2 motifs contain a binding site for Grb2 at the second tyrosine. (PMID:16729043)
• the neuregulin/ERBB3 signaling pathway is constitutively activated in clear cell sarcoma of soft tissue (PMID:16867224)
• Sox10-regulated overexpression of ErbB3 may be driving growth in pilocytic astrocytoma. (PMID:16896310)
• failure to find genetic association suggests that the differential expression of ERBB3 in schizophrenia may be environmentally driven, or involve cis- or trans-acting genetic factors beyond the boundaries of the gene itself (PMID:16958035)
• enhanced signaling from the HER2/neu-HER3 pathway has a role in growth of tumors treated with fulvestrant in the presence of physiologic estradiol: pertuzumab partially inhibits growth and HER2/neu with HER3 interact in vivo (PMID:17203234)
• Neuregulin 1-induced protein stability cascade involving USP8 and Nrdp1 mediates the down-regulation of ErbB3 (PMID:17210635)
• there were no significant association between the polymorphisms or haplotypes of ERBB3 and schizophrenia; study shows that ERBB3 does not play a major role in conferring susceptibility to schizophrenia in the Japanese population (PMID:17275115)
• findings show that amplification of MET causes gefitinib resistance in lung cancer by driving ERBB3 (HER3)-dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors (PMID:17463250)
• HER3 signaling pathway plays an important role in the biological behavior of certain non-small cell lung cancers. (PMID:17627612)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	erbb3a	ENSDARG00000006202
danio_rerio	erbb3b	ENSDARG00000036993
mus_musculus	Erbb3	ENSMUSG00000018166
rattus_norvegicus	Erbb3	ENSRNOG00000004964

Paralogs (53): INSRR (ENSG00000027644), MUSK (ENSG00000030304), FLT4 (ENSG00000037280), EPHA3 (ENSG00000044524), ROS1 (ENSG00000047936), LTK (ENSG00000062524), TIE1 (ENSG00000066056), FGFR2 (ENSG00000066468), FGFR3 (ENSG00000068078), EPHA8 (ENSG00000070886), FGFR1 (ENSG00000077782), EPHA6 (ENSG00000080224), TYRO3 (ENSG00000092445), FLT1 (ENSG00000102755), MET (ENSG00000105976), EPHB6 (ENSG00000106123), PDGFRB (ENSG00000113721), EPHA4 (ENSG00000116106), TEK (ENSG00000120156), FLT3 (ENSG00000122025), KDR (ENSG00000128052), EPHB2 (ENSG00000133216), PDGFRA (ENSG00000134853), EPHA7 (ENSG00000135333), IGF1R (ENSG00000140443), NTRK3 (ENSG00000140538), ERBB2 (ENSG00000141736), EPHA2 (ENSG00000142627), EPHA5 (ENSG00000145242), EGFR (ENSG00000146648), EPHA1 (ENSG00000146904), NTRK2 (ENSG00000148053), MERTK (ENSG00000153208), EPHB1 (ENSG00000154928), KIT (ENSG00000157404), FGFR4 (ENSG00000160867), DDR2 (ENSG00000162733), RYK (ENSG00000163785), MST1R (ENSG00000164078), LMTK2 (ENSG00000164715)

Protein

Protein identifiers

Receptor tyrosine-protein kinase erbB-3 — P21860 (reviewed: P21860)

Alternative names: Proto-oncogene-like protein c-ErbB-3, Tyrosine kinase-type cell surface receptor HER3

All UniProt accessions (9): P21860, A0A2R8Y6T4, B3KWG5, B4DGQ7, F8VRI5, F8VRL0, F8VW48, F8VYK4, O75812

UniProt curated annotations — full annotation on UniProt →

Function. Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins. Binds to neuregulin-1 (NRG1) and is activated by it; ligand-binding increases phosphorylation on tyrosine residues and promotes its association with the p85 subunit of phosphatidylinositol 3-kinase. May also be activated by CSPG5. Involved in the regulation of myeloid cell differentiation.

Subunit / interactions. Monomer and homodimer. Heterodimer with each of the other ERBB receptors (Potential). Interacts with CSPG5. Interacts with GRB7. Interacts with MUC1. Interacts with MYOC. Interacts with isoform 2 of PA2G4. Found in a ternary complex with NRG1 and ITGAV:ITGB3 or ITGA6:ITGB4.

Subcellular location. Cell membrane Secreted.

Tissue specificity. Epithelial tissues and brain.

Post-translational modifications. Autophosphorylated. Ligand-binding increases phosphorylation on tyrosine residues and promotes its association with the p85 subunit of phosphatidylinositol 3-kinase.

Disease relevance. Lethal congenital contracture syndrome 2 (LCCS2) [MIM:607598] A form of lethal congenital contracture syndrome, an autosomal recessive disorder characterized by degeneration of anterior horn neurons, extreme skeletal muscle atrophy, and congenital non-progressive joint contractures (arthrogryposis). The contractures can involve the upper or lower limbs and/or the vertebral column, leading to various degrees of flexion or extension limitations evident at birth. LCCS2 patients manifest craniofacial/ocular findings, lack of hydrops, multiple pterygia, and fractures, as well as a normal duration of pregnancy and a unique feature of a markedly distended urinary bladder (neurogenic bladder defect). The phenotype suggests a spinal cord neuropathic etiology. The disease is caused by variants affecting the gene represented in this entry. Erythroleukemia, familial (FERLK) [MIM:133180] An autosomal dominant myeloproliferative disorder characterized by neoplastic proliferation of erythroblastic and myeloblastic elements with atypical erythroblasts and myeloblasts in the peripheral blood. Disease penetrance is incomplete. Disease susceptibility may be associated with variants affecting the gene represented in this entry. Visceral neuropathy, familial, 1, autosomal recessive (VSCN1) [MIM:243180] An autosomal recessive disorder characterized by intestinal dysmotility due to aganglionosis (Hirschsprung disease), hypoganglionosis, and/or chronic intestinal pseudoobstruction. Additional variable features are progressive peripheral neuropathy, arthrogryposis, hypoplasia or aplasia of the olfactory bulb and of the external auditory canals, microtia or anotia, and facial dysmorphism. Some patients present structural cardiac anomalies and arthrogryposis with multiple pterygia. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The cytoplasmic part of the receptor may interact with the SH2 or SH3 domains of many signal-transducing proteins.

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
P21860-1	1, long form	yes
P21860-2	2, short form
P21860-3	3
P21860-4	4
P21860-5	5

RefSeq proteins (2): NP_001005915, NP_001973* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000494	Rcpt_L-dom	Domain
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR006211	Furin-like_Cys-rich_dom	Domain
IPR006212	Furin_repeat	Repeat
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR016245	Tyr_kinase_EGF/ERB/XmrK_rcpt	Family
IPR032778	GF_recep_IV	Domain
IPR036941	Rcpt_L-dom_sf	Homologous_superfamily
IPR050122	RTK	Family

Pfam: PF00757, PF01030, PF07714, PF14843

Enzyme classification (BRENDA):

• EC 2.7.10.1 — receptor protein-tyrosine kinase (BRENDA: 44 organisms, 214 substrates, 574 inhibitors, 11 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0011–0.129	4
AC-DYFE-6-CHLORO-W-NHME	0.0051	1
AC-DYFGW-NHME	0.07	1
YFEW	0.232	1

Catalyzed reactions (Rhea), 1 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)

UniProt features (185 total): strand 61, helix 33, disulfide bond 23, sequence variant 19, turn 10, glycosylation site 10, splice variant 6, sequence conflict 5, binding site 4, modified residue 2, topological domain 2, region of interest 2, mutagenesis site 2, signal peptide 1, chain 1, transmembrane region 1, domain 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

23 structures.

PDB	Method	Resolution (Å)
7BHF	X-RAY DIFFRACTION	2
7BHE	X-RAY DIFFRACTION	2.3
7D85	X-RAY DIFFRACTION	2.5
6OP9	X-RAY DIFFRACTION	2.5
1M6B	X-RAY DIFFRACTION	2.6
4LEO	X-RAY DIFFRACTION	2.64
3KEX	X-RAY DIFFRACTION	2.8
3LMG	X-RAY DIFFRACTION	2.8
9I1Q	X-RAY DIFFRACTION	2.8
7MN5	ELECTRON MICROSCOPY	2.93
8YRY	ELECTRON MICROSCOPY	2.93
4RIY	X-RAY DIFFRACTION	2.98
6KBI	X-RAY DIFFRACTION	3
7MN6	ELECTRON MICROSCOPY	3.09
4RIW	X-RAY DIFFRACTION	3.1
4RIX	X-RAY DIFFRACTION	3.1
5CUS	X-RAY DIFFRACTION	3.2
4P59	X-RAY DIFFRACTION	3.4
5O4O	X-RAY DIFFRACTION	3.4
7MN8	ELECTRON MICROSCOPY	3.45
3P11	X-RAY DIFFRACTION	3.7
5O7P	X-RAY DIFFRACTION	4.5
2L9U	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P21860-F1	72.90	0.48

Antibody-complex structures (SAbDab): 10 — 3P11, 4LEO, 4P59, 5CUS, 5O4O, 5O7P, 7D85, 7MN8, 8YRY, 9I1Q

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): 834 (proton acceptor)

Ligand- & substrate-binding residues (4): 715–723; 742; 788–790; 834–839

Post-translational modifications (2): 686, 982

Disulfide bonds (23): 29–56, 156–183, 186–194, 190–202, 210–218, 214–226, 227–235, 231–243, 246–255, 259–286, 290–301, 305–320, 323–327, 500–509, 504–517, 520–529, 533–549, 552–565, 556–573, 576–585 …

Glycosylation sites (10): 126, 250, 353, 408, 414, 437, 469, 522, 566, 616

Mutagenesis-validated functional residues (2):

Position	Phenotype
742	strongly reduced autophosphorylation.
868	strongly reduced tyrosine phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-1227986	Signaling by ERBB2
R-HSA-1236394	Signaling by ERBB4
R-HSA-1250196	SHC1 events in ERBB2 signaling
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1306955	GRB7 events in ERBB2 signaling
R-HSA-1358803	Downregulation of ERBB2:ERBB3 signaling
R-HSA-1963642	PI3K events in ERBB2 signaling
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6785631	ERBB2 Regulates Cell Motility
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-8847993	ERBB2 Activates PTK6 Signaling
R-HSA-8863795	Downregulation of ERBB2 signaling
R-HSA-9664565	Signaling by ERBB2 KD Mutants
R-HSA-9665686	Signaling by ERBB2 TMD/JMD mutants

MSigDB gene sets: 550 (showing top): GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_REGULATION_OF_CARDIAC_MUSCLE_TISSUE_DEVELOPMENT, GOBP_ENDOCARDIAL_CUSHION_DEVELOPMENT, GCANCTGNY_MYOD_Q6, AREB6_03, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_GLIAL_CELL_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, MCBRYAN_PUBERTAL_TGFB1_TARGETS_DN, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_NEUROGENESIS

GO Biological Process (33): endocardial cushion development (GO:0003197), negative regulation of cell adhesion (GO:0007162), signal transduction (GO:0007165), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), epidermal growth factor receptor signaling pathway (GO:0007173), peripheral nervous system development (GO:0007422), heart development (GO:0007507), negative regulation of signal transduction (GO:0009968), positive regulation of gene expression (GO:0010628), Schwann cell differentiation (GO:0014037), Schwann cell development (GO:0014044), cranial nerve development (GO:0021545), neuron differentiation (GO:0030182), ERBB2-ERBB3 signaling pathway (GO:0038133), wound healing (GO:0042060), regulation of cell population proliferation (GO:0042127), myelination (GO:0042552), negative regulation of apoptotic process (GO:0043066), positive regulation of MAPK cascade (GO:0043410), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), negative regulation of neuron apoptotic process (GO:0043524), positive regulation of epithelial cell proliferation (GO:0050679), negative regulation of secretion (GO:0051048), neuron apoptotic process (GO:0051402), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), positive regulation of cardiac muscle tissue development (GO:0055025), positive regulation of calcineurin-NFAT signaling cascade (GO:0070886), motor neuron apoptotic process (GO:0097049), extrinsic apoptotic signaling pathway in absence of ligand (GO:0097192), negative regulation of motor neuron apoptotic process (GO:2000672), protein phosphorylation (GO:0006468), cell development (GO:0048468), regulation of developmental process (GO:0050793)

GO Molecular Function (18): protein kinase activity (GO:0004672), transmembrane signaling receptor activity (GO:0004888), ATP binding (GO:0005524), growth factor binding (GO:0019838), protein tyrosine kinase activator activity (GO:0030296), ubiquitin protein ligase binding (GO:0031625), neuregulin receptor activity (GO:0038131), neuregulin binding (GO:0038132), identical protein binding (GO:0042802), ErbB-3 class receptor binding (GO:0043125), protein heterodimerization activity (GO:0046982), nucleotide binding (GO:0000166), protein tyrosine kinase activity (GO:0004713), transmembrane receptor protein tyrosine kinase activity (GO:0004714), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), signaling receptor activity (GO:0038023)

GO Cellular Component (11): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), basal plasma membrane (GO:0009925), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), lateral plasma membrane (GO:0016328), ERBB3:ERBB2 complex (GO:0038143), signaling receptor complex (GO:0043235), extracellular region (GO:0005576), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Signaling by ERBB2	6
Signaling by Receptor Tyrosine Kinases	2
Signaling by ERBB2 in Cancer	2
Intracellular signaling by second messengers	1
Downregulation of ERBB2 signaling	1
PI3K/AKT Signaling in Cancer	1
MAPK1/MAPK3 signaling	1
Negative regulation of the PI3K/AKT network	1
Signaling by PTK6	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
plasma membrane region	3
regulation of cellular process	2
protein binding	2
protein tyrosine kinase activity	2
plasma membrane	2
heart development	1
mesenchyme development	1
cell adhesion	1
regulation of cell adhesion	1
negative regulation of cellular process	1
cell communication	1
cellular process	1
signaling	1
cellular response to stimulus	1
enzyme-linked receptor protein signaling pathway	1
ERBB signaling pathway	1
nervous system development	1
system development	1
animal organ development	1
circulatory system development	1
signal transduction	1
regulation of signal transduction	1
negative regulation of cell communication	1
negative regulation of signaling	1
negative regulation of response to stimulus	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
peripheral nervous system development	1
glial cell differentiation	1
Schwann cell differentiation	1
glial cell development	1
nerve development	1
cell differentiation	1
generation of neurons	1
ERBB2 signaling pathway	1
ERBB3 signaling pathway	1
response to wounding	1
tissue regeneration	1

Protein interactions and networks

STRING

3640 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERBB3	NRG1	P98202	999
ERBB3	EGF	P01133	998
ERBB3	NRG2	O14511	998
ERBB3	HBEGF	Q99075	986
ERBB3	EGFR	P00533	984
ERBB3	ERBB2	P04626	984
ERBB3	ERBB4	Q15303	983
ERBB3	PA2G4	Q9UQ80	983
ERBB3	TGFA	P01135	982
ERBB3	AREG	P15514	981
ERBB3	SHC1	P29353	976
ERBB3	GRB2	P29354	976
ERBB3	NRG4	Q8WWG1	968
ERBB3	BTC	P35070	960
ERBB3	EREG	O14944	952

IntAct

383 interactions, top by confidence:

A	B	Type	Score
ERBB2	ERBB3	psi-mi:“MI:0915”(physical association)	0.970
ERBB3	ERBB2	psi-mi:“MI:0915”(physical association)	0.970
ERBB3	ERBB2	psi-mi:“MI:0914”(association)	0.970
ERBB2	ERBB3	psi-mi:“MI:0407”(direct interaction)	0.970
ERBB2	ERBB3	psi-mi:“MI:0914”(association)	0.970
ERBB2	EGFR	psi-mi:“MI:0914”(association)	0.950
EGFR	ERBB3	psi-mi:“MI:0915”(physical association)	0.920
PIK3R1	ERBB3	psi-mi:“MI:0915”(physical association)	0.920

BioGRID (488): ERBB3 (Affinity Capture-MS), HLA-DPA1 (Affinity Capture-MS), UQCR10 (Affinity Capture-MS), B3GALTL (Affinity Capture-MS), PDF (Affinity Capture-MS), TUBA4A (Affinity Capture-MS), TUBB8 (Affinity Capture-MS), HLA-A (Affinity Capture-MS), YBEY (Affinity Capture-MS), SLC31A1 (Affinity Capture-MS), EIF1AX (Affinity Capture-MS), ERBB3 (Biochemical Activity), ERBB2 (Co-localization), HLA-A (Affinity Capture-MS), HLA-B (Affinity Capture-MS)

ESM2 similar proteins: A4IIY1, A5PK27, E7FAM5, O94806, O94844, P21860, P42694, P50747, P97711, Q15139, Q1PSW8, Q2TBA3, Q2YDF9, Q496Y0, Q4KLT0, Q5BIM1, Q5RB22, Q5RFV4, Q5XIS9, Q60553, Q62101, Q62921, Q6DDJ3, Q6DFV5, Q6DH94, Q6DJB3, Q6DLV9, Q6NYU2, Q6PFY8, Q7T0P6, Q7Z419, Q80WC9, Q8BKD6, Q8BWW9, Q8BZ03, Q8HXH0, Q8K1Y2, Q8R023, Q91009, Q920N2

Diamond homologs: A0M8R7, A0M8S8, O08680, O13146, O18735, O35346, O54967, O73875, O73878, P00519, P00520, P00521, P00533, P00534, P00535, P04412, P04626, P06494, P07949, P09759, P0CY46, P10447, P11273, P13387, P13388, P16056, P21860, P24348, P28693, P29317, P29318, P29319, P29320, P29323, P34152, P42684, P53356, P54755, P54756, P54757

SIGNOR signaling

25 interactions.

A	Effect	B	Mechanism
ERBB3	up-regulates	GRB2	binding
ERBB3	“up-regulates quantity by expression”	AR	“transcriptional regulation”
LRIG1	down-regulates	ERBB3	ubiquitination
ERBB3	up-regulates	PIK3CA	binding
ERBB3	up-regulates	PIK3CB	binding
ERBB3	up-regulates	PIK3CD	binding
ERBB3	up-regulates	PIK3CG	binding
EREG	up-regulates	ERBB3	binding
sapitinib	down-regulates	ERBB3	“chemical inhibition”
ERBB3	up-regulates	PI3K	binding
TWIST2	“down-regulates quantity by repression”	ERBB3	“transcriptional regulation”
NRG1	up-regulates	ERBB3	binding
NRG2	up-regulates	ERBB3	binding
RNF41	“down-regulates quantity by destabilization”	ERBB3	polyubiquitination
ERBB2	“up-regulates activity”	ERBB3	phosphorylation
ROR1	“up-regulates activity”	ERBB3	phosphorylation
EGFR	up-regulates	ERBB3	phosphorylation
ERBB2	up-regulates	ERBB3	binding
CDK5	“up-regulates activity”	ERBB3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 123 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
PI3K events in ERBB2 signaling	6	50.4×	2e-07
GAB1 signalosome	5	39.6×	7e-06
Signaling by ALK	5	35.7×	1e-05
Downregulation of ERBB2 signaling	7	33.3×	2e-07
Signaling by ERBB2 KD Mutants	6	31.7×	2e-06
Signaling by ERBB2	7	30.3×	2e-07
SHC1 events in ERBB2 signaling	5	29.7×	3e-05
Downstream signal transduction	6	28.6×	4e-06

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine dephosphorylation	5	40.0×	2e-05
phosphatidylinositol dephosphorylation	6	35.0×	6e-06
protein dephosphorylation	13	26.0×	3e-12
peptidyl-tyrosine phosphorylation	6	22.8×	4e-05
cellular response to epidermal growth factor stimulus	7	20.1×	1e-05
epidermal growth factor receptor signaling pathway	8	17.9×	6e-06
phosphatidylinositol 3-kinase/protein kinase B signal transduction	7	13.3×	1e-04
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	9	6.4×	1e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 11 cancer types — BLCA, BRCA, CESC, CHOL, COADREAD, NBL, PRAD, STAD, UCEC, UCS, UTUC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	15
Uncertain significance	89
Likely benign	50
Benign	37

Top pathogenic / likely-pathogenic (22)

Variant ID	HGVS	Classification
1188813	NM_001982.4(ERBB3):c.3297del (p.His1100fs)	Pathogenic
2572087	NM_001982.4(ERBB3):c.1914-7C>G	Pathogenic
2572088	NM_001982.4(ERBB3):c.2942_2945del	Pathogenic
2582246	NM_001982.4(ERBB3):c.307C>T (p.Arg103Cys)	Pathogenic
2582247	NM_001982.4(ERBB3):c.2782G>A (p.Glu928Lys)	Pathogenic
2582287	NM_001982.4(ERBB3):c.180G>A (p.Met60Ile)	Pathogenic
376410	NM_001982.4(ERBB3):c.310G>A (p.Val104Met)	Pathogenic
1188814	NM_001982.4(ERBB3):c.2359A>C (p.Thr787Pro)	Likely pathogenic
1188815	NM_001982.4(ERBB3):c.2695G>A (p.Val899Met)	Likely pathogenic
12572	NM_001982.4(ERBB3):c.1184-9A>G	Likely pathogenic
2627242	NM_001982.4(ERBB3):c.3202-2A>G	Likely pathogenic
2628640	NM_001982.4(ERBB3):c.1330C>T (p.Arg444Ter)	Likely pathogenic
2631098	NM_001982.4(ERBB3):c.1881_1891del (p.Asp628fs)	Likely pathogenic
3574998	NM_001982.4(ERBB3):c.83-2A>G	Likely pathogenic
3574999	NM_001982.4(ERBB3):c.237G>A (p.Trp79Ter)	Likely pathogenic
3575000	NM_001982.4(ERBB3):c.3223del (p.Ser1075fs)	Likely pathogenic
374608	NM_001982.4(ERBB3):c.2274+1G>A	Likely pathogenic
3764552	NM_001982.4(ERBB3):c.234+2T>C	Likely pathogenic
4293323	NM_001982.4(ERBB3):c.874+1G>A	Likely pathogenic
4805825	NM_001982.4(ERBB3):c.547_547+2del	Likely pathogenic
4845779	NM_001982.4(ERBB3):c.2442G>A (p.Trp814Ter)	Likely pathogenic
978710	NM_001982.4(ERBB3):c.1253T>C (p.Ile418Thr)	Likely pathogenic

SpliceAI

4325 predictions. Top by Δscore:

Variant	Effect	Δscore
12:56083748:CAGTG:C	acceptor_loss	1.0000
12:56083749:A:AG	acceptor_gain	1.0000
12:56083750:G:GA	acceptor_gain	1.0000
12:56083750:GT:G	acceptor_gain	1.0000
12:56083750:GTGT:G	acceptor_gain	1.0000
12:56083899:GCAG:G	donor_gain	1.0000
12:56083900:CAGGT:C	donor_loss	1.0000
12:56084976:A:AG	acceptor_gain	1.0000
12:56084977:T:G	acceptor_gain	1.0000
12:56084978:A:AG	acceptor_gain	1.0000
12:56084978:AATCT:A	acceptor_gain	1.0000
12:56084982:T:TA	acceptor_gain	1.0000
12:56084993:A:AG	acceptor_gain	1.0000
12:56084993:AGTG:A	acceptor_gain	1.0000
12:56084994:G:GG	acceptor_gain	1.0000
12:56084994:GT:G	acceptor_gain	1.0000
12:56084994:GTGG:G	acceptor_gain	1.0000
12:56085099:G:GT	donor_gain	1.0000
12:56085268:C:G	donor_gain	1.0000
12:56086378:G:GT	donor_gain	1.0000
12:56086529:A:AG	acceptor_gain	1.0000
12:56086530:G:GG	acceptor_gain	1.0000
12:56086530:GA:G	acceptor_gain	1.0000
12:56086652:AAGCT:A	donor_gain	1.0000
12:56086654:GCT:G	donor_gain	1.0000
12:56086655:CT:C	donor_gain	1.0000
12:56086657:G:GG	donor_gain	1.0000
12:56087638:GACAT:G	donor_gain	1.0000
12:56087791:A:AG	acceptor_gain	1.0000
12:56087791:ATAGT:A	acceptor_gain	1.0000

AlphaMissense

8783 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:56083759:G:T	G31W	1.000
12:56083835:G:A	C56Y	1.000
12:56083856:T:A	L63H	1.000
12:56083856:T:C	L63P	1.000
12:56085013:G:T	G85C	1.000
12:56085014:G:T	G85V	1.000
12:56085023:T:C	L88P	1.000
12:56085036:T:A	N92K	1.000
12:56085036:T:G	N92K	1.000
12:56085126:C:A	N122K	1.000
12:56085126:C:G	N122K	1.000
12:56086565:C:A	N152K	1.000
12:56086565:C:G	N152K	1.000
12:56086598:G:C	W163C	1.000
12:56086598:G:T	W163C	1.000
12:56087614:G:C	W195C	1.000
12:56087614:G:T	W195C	1.000
12:56088144:T:A	C286S	1.000
12:56088144:T:C	C286R	1.000
12:56088145:G:C	C286S	1.000
12:56088156:T:A	C290S	1.000
12:56088156:T:C	C290R	1.000
12:56088157:G:C	C290S	1.000
12:56088569:T:A	C301S	1.000
12:56088569:T:C	C301R	1.000
12:56088570:G:A	C301Y	1.000
12:56088570:G:C	C301S	1.000
12:56088571:T:G	C301W	1.000
12:56088581:T:A	C305S	1.000
12:56088581:T:C	C305R	1.000

dbSNP variants (sampled 300 via entrez): RS1000186509 (12:56092116 G>A), RS1000237251 (12:56092473 G>GTTA), RS1000398584 (12:56086385 T>C), RS1000415301 (12:56093841 T>A,G), RS1000451758 (12:56088487 G>A,T), RS1000586707 (12:56088920 G>A), RS1000923648 (12:56079628 T>G), RS1001350403 (12:56080123 T>A,G), RS1001510680 (12:56095933 C>T), RS1001517553 (12:56081222 C>T), RS1001575378 (12:56080811 G>A,C,T), RS1001683349 (12:56079785 AGT>A), RS1001747838 (12:56100840 T>C), RS1001854934 (12:56095151 A>G), RS1001897990 (12:56095543 A>C,T)

Disease associations

OMIM: gene MIM:190151 | disease phenotypes: MIM:133180, MIM:607598, MIM:243180, MIM:109800, MIM:253310

GenCC curated gene-disease

Disease	Classification	Inheritance
lethal congenital contracture syndrome 2	Strong	Autosomal recessive
visceral neuropathy, familial, 1, autosomal recessive	Strong	Autosomal recessive
Hirschsprung disease	Supportive	Autosomal dominant

Mondo (8): erythroleukemia, familial, susceptibility to (MONDO:0007573), lethal congenital contracture syndrome 2 (MONDO:0011868), visceral neuropathy, familial, 1, autosomal recessive (MONDO:8000011), visceral neuropathy, familial (MONDO:0023961), prostate cancer (MONDO:0008315), urinary bladder cancer (MONDO:0001187), lethal congenital contracture syndrome 1 (MONDO:0009670), Hirschsprung disease (MONDO:0018309)

Orphanet (6): Lethal congenital contracture syndrome type 2 (Orphanet:137776), Acute erythroid leukemia (Orphanet:318), Neuronal intestinal pseudoobstruction (Orphanet:99811), Familial prostate cancer (Orphanet:1331), Lethal congenital contracture syndrome type 1 (Orphanet:1486), NON RARE IN EUROPE: Bladder cancer (Orphanet:157980)

HPO phenotypes

59 total (30 of 59 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000126	Hydronephrosis
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000413	Atresia of the external auditory canal
HP:0000508	Ptosis
HP:0000969	Edema
HP:0001260	Dysarthria
HP:0001284	Areflexia
HP:0001510	Growth delay
HP:0001531	Failure to thrive in infancy
HP:0001558	Decreased fetal movement
HP:0001561	Polyhydramnios
HP:0001629	Ventricular septal defect
HP:0001644	Dilated cardiomyopathy
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001903	Anemia
HP:0001909	Leukemia
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002017	Nausea and vomiting
HP:0002019	Constipation
HP:0002027	Abdominal pain
HP:0002066	Gait ataxia
HP:0002240	Hepatomegaly
HP:0002251	Aganglionic megacolon
HP:0002253	Colonic diverticula

GWAS associations

28 associations (top):

Study	Trait	p-value
GCST000038_4	Type 1 diabetes	2.000000e-20
GCST000043_4	Type 1 diabetes	1.000000e-11
GCST000141_1	Type 1 diabetes	9.000000e-10
GCST000258_9	Type 1 diabetes	3.000000e-16
GCST000392_2	Type 1 diabetes	2.000000e-25
GCST001191_6	Type 1 diabetes	3.000000e-27
GCST001670_1	Vitiligo	8.000000e-12
GCST001762_469	Obesity-related traits	5.000000e-07
GCST002774_24	Cognitive function	3.000000e-07
GCST003144_7	Polycystic ovary syndrome	2.000000e-07
GCST003988_25	Hypothyroidism	8.000000e-08
GCST004367_1	Anorexia nervosa	4.000000e-09
GCST004866_11	Alopecia areata	4.000000e-09
GCST007563_23	Allergic disease (asthma, hay fever or eczema)	4.000000e-10
GCST007564_9	Asthma or allergic disease (pleiotropy)	1.000000e-13
GCST007603_18	Smoking initiation	3.000000e-08
GCST007798_148	Asthma	8.000000e-25
GCST007799_4	Asthma (adult onset)	4.000000e-15
GCST008916_124	Asthma	1.000000e-16
GCST009524_114	Household income (MTAG)	3.000000e-08
GCST009798_45	Asthma	1.000000e-15
GCST009875_4	Type 1 diabetes	1.000000e-18
GCST010002_217	Refractive error	6.000000e-174
GCST010571_56	Autoimmune thyroid disease	2.000000e-11
GCST010703_297	Brain morphology (MOSTest)	4.000000e-10
GCST011156_1	Body mass index	1.000000e-08
GCST011703_9	Smoking initiation	2.000000e-08
GCST90000047_182	Age at first sexual intercourse	8.000000e-10

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004626	IGFBP-3 measurement
EFO:0004337	intelligence
EFO:0005670	smoking initiation
EFO:1002011	adult onset asthma
EFO:0009695	household income
EFO:0004346	neuroimaging measurement
EFO:0004340	body mass index
EFO:0009749	age at first sexual intercourse measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439
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
C565039	Erythroleukemia, Familial (supp.)
C564369	Lethal Congenital Contracture Syndrome 2 (supp.)
C537194	Lethal congenital contracture syndrome 1 (supp.)
C537394	Neuronal intestinal pseudoobstruction (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2363049 (PROTEIN FAMILY), CHEMBL4630723 (PROTEIN COMPLEX), CHEMBL5838 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

23 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 440,115 (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
CHEMBL4650319	MOBOCERTINIB	4	929
CHEMBL1173655	AFATINIB	4	15,144
CHEMBL180022	NERATINIB	4	9,404
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3353410	OSIMERTINIB	4	8,898
CHEMBL5416410	DASATINIB	4	655
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL554	LAPATINIB	4	69,326
CHEMBL939	GEFITINIB	4	117,814
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL3545308	ROCILETINIB	3	1,729
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL491473	CEDIRANIB	3	9,098
CHEMBL545315	CANERTINIB DIHYDROCHLORIDE	3	881
CHEMBL603469	LESTAURTINIB	3
CHEMBL587723	AEE-788	2	2,697
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL2408045	SAPITINIB	2	1,460
CHEMBL3786098	PF-06459988	2	335
CHEMBL3989970	MAVELERTINIB	2
CHEMBL572878	TOZASERTIB	2
CHEMBL1614725	TAK-285	1

Clinical evidence (CIViC)

Drug × variant × indication: 18 predictive associations from 18 curated evidence items; also 3 functional, 2 oncogenic.

Variant	Therapy	Indication	Effect	Level	CIViC
ERBB2 Mutation OR ERBB3 Mutation	Trastuzumab + Pertuzumab	Colorectal Cancer	Sensitivity/Response	CIViC B	EID11669
ERBB3 G284R	Afatinib	Transitional Cell Carcinoma	Sensitivity/Response	CIViC B	EID1748
ERBB3 Overexpression	Lapatinib	Breast Cancer	Sensitivity/Response	CIViC B	EID3053
ERBB3 R103G	Afatinib	Transitional Cell Carcinoma	Sensitivity/Response	CIViC B	EID1747
ERBB3 V104M	Afatinib	Transitional Cell Carcinoma	Sensitivity/Response	CIViC B	EID1746
ERBB3 Overexpression	Cetuximab	Colorectal Cancer	Resistance	CIViC B	EID729
ERBB3 Overexpression	Trastuzumab Emtansine	Her2-receptor Positive Breast Cancer	Resistance	CIViC B	EID8707
ERBB3 G284R	Lapatinib + Trastuzumab	Breast Cancer	Sensitivity/Response	CIViC C	EID7244
ERBB3 EXPRESSION	Pertuzumab	Melanoma	Sensitivity/Response	CIViC D	EID3051
ERBB3 EXPRESSION	Anti-ErbB3 Monoclonal Antibody AV-203	Cancer	Sensitivity/Response	CIViC D	EID862
ERBB3 EXPRESSION	9F7-F11 + Pertuzumab	Pancreatic Ductal Adenocarcinoma	Sensitivity/Response	CIViC D	EID865
ERBB3 G284R	Duligotuzumab + Trastuzumab + Pertuzumab + Lapatinib	Cancer	Sensitivity/Response	CIViC D	EID9684
ERBB3 Overexpression	Selumetinib + Afatinib	Cancer	Sensitivity/Response	CIViC D	EID1152
ERBB3 Overexpression	Pertuzumab	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC D	EID7804
ERBB3 V104M	Pertuzumab + Trastuzumab + Lapatinib + Duligotuzumab	Cancer	Sensitivity/Response	CIViC D	EID9670
ERBB3 V855A	Afatinib + Pertuzumab	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC D	EID1845
ERBB3 Overexpression	Selumetinib + HER2 Inhibitor CP-724 + 714 + Gefitinib	Cancer	Resistance	CIViC D	EID1153
ERBB3 Overexpression	Trametinib + Selumetinib	Uveal Melanoma	Resistance	CIViC D	EID3050

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2229046	Efficacy	3	carboplatin;docetaxel;trastuzumab	Breast Neoplasms
rs773123	Efficacy	3	carboplatin;docetaxel;trastuzumab	Breast Neoplasms

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2229046	ERBB3	3	3.00	1	carboplatin;docetaxel;trastuzumab
rs773123	ERBB3	3	2.50	1	carboplatin;docetaxel;trastuzumab

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Type I RTKs: ErbB (epidermal growth factor) receptor family

Most potent curated ligand interactions (10 total), top 10:

Ligand	Action	Affinity	Parameter
elgemtumab	Binding	11.4	pKd
zenocutuzumab	Antagonist	10.46	pEC50
neuregulin-1		9.26	pIC50
seribantumab	Binding	9.11	pKd
patritumab deruxtecan	Binding	9.0	pKd
istiratumab	Binding	9.0	pKd
sapitinib	Inhibition	8.4	pIC50
MM-111	Binding	7.81	pKd
TX1-85-1	Binding	7.64	pIC50
TX2-121-1	Inhibition	7.31	pIC50

Binding affinities (BindingDB)

12 measured of 12 human assays (12 total across all organisms); most potent 12 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL3763405	IC50	4.6 nM
CHEMBL3763627	IC50	5.4 nM
CHEMBL3765425	IC50	5.7 nM
CHEMBL3765815	IC50	6 nM
CHEMBL3763796	IC50	10 nM
CHEMBL3763757	IC50	11 nM
CHEMBL3765263	IC50	12 nM
CHEMBL3764603	IC50	15 nM
CHEMBL3764312	IC50	17 nM
CHEMBL3763701	IC50	33 nM
CHEMBL3764589	IC50	66 nM
CHEMBL3765789	IC50	159 nM

ChEMBL bioactivities

152 potent at pChembl≥5 of 162 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.16	IC50	0.69	nM	CHEMBL2387001
9.11	Kd	0.77	nM	BOSUTINIB
9.05	IC50	0.89	nM	CHEMBL2387000
9.00	IC50	1	nM	CHEMBL3883534
8.92	IC50	1.2	nM	CHEMBL2386999
8.92	IC50	1.2	nM	CHEMBL4228518
8.77	IC50	1.7	nM	CHEMBL3622673
8.77	IC50	1.7	nM	CHEMBL4225777
8.72	IC50	1.9	nM	CHEMBL4226676
8.70	IC50	2	nM	AEE-788
8.70	IC50	2	nM	CHEMBL3608429
8.70	IC50	2	nM	CHEMBL4216679
8.70	IC50	2	nM	CHEMBL4226151
8.68	IC50	2.1	nM	OSIMERTINIB
8.62	IC50	2.4	nM	CHEMBL4225565
8.59	IC50	2.6	nM	CHEMBL4227084
8.52	IC50	3	nM	CHEMBL3086102
8.48	IC50	3.3	nM	MOBOCERTINIB
8.40	IC50	4	nM	SAPITINIB
8.40	IC50	4	nM	MAVELERTINIB
8.38	IC50	4.2	nM	CHEMBL4225951
8.38	IC50	4.2	nM	CHEMBL4225306
8.34	IC50	4.6	nM	CHEMBL2386998
8.30	IC50	5	nM	CHEMBL3985592
8.30	IC50	5	nM	CHEMBL3956925
8.24	IC50	5.8	nM	CHEMBL4226937
8.24	IC50	5.7	nM	CHEMBL1923009
8.14	IC50	7.2	nM	CHEMBL1923022
8.11	Kd	7.7	nM	NERATINIB
8.11	IC50	7.7	nM	CHEMBL1923000
8.05	IC50	9	nM	CHEMBL3608432
8.04	IC50	9.2	nM	CHEMBL1923003
8.02	IC50	9.5	nM	CHEMBL1923006
8.00	IC50	10	nM	ERLOTINIB
8.00	IC50	10	nM	CHEMBL1923019
7.85	IC50	14	nM	CANERTINIB DIHYDROCHLORIDE
7.82	IC50	15	nM	CHEMBL1923010
7.82	IC50	15	nM	CHEMBL1923020
7.75	IC50	18	nM	CHEMBL4288300
7.75	Kd	18	nM	DASATINIB
7.75	IC50	18	nM	CHEMBL1923001
7.70	IC50	20	nM	CHEMBL3973190
7.70	IC50	20	nM	CHEMBL1922999
7.68	IC50	21	nM	PF-06459988
7.68	IC50	21	nM	CHEMBL4282460
7.66	IC50	22	nM	CHEMBL1923013
7.64	IC50	23	nM	CHEMBL5285282
7.64	IC50	23	nM	TAK-285
7.57	IC50	27	nM	CHEMBL4283970
7.57	IC50	27	nM	CHEMBL1922900

PubChem BioAssay actives

141 with measured affinity, of 432 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1-[3-(4-amino-7-cyclopentylpyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl]-3-(2-methoxy-5-methylphenyl)urea	748805: Inhibition of human EGFR extracellular domain/TIE2 intracellular domain transfected in mouse NIH/3T3 cells assessed as phosphotyrosine level preincubated for 60 mins followed by EGF stimulation by DELFIA assay	ic50	0.0007	uM
Bosutinib	624851: Binding constant for ERBB3 kinase domain	kd	0.0008	uM
1-[3-(4-amino-7-cyclopentylpyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl]-3-(2-fluoro-5-methylphenyl)urea	748805: Inhibition of human EGFR extracellular domain/TIE2 intracellular domain transfected in mouse NIH/3T3 cells assessed as phosphotyrosine level preincubated for 60 mins followed by EGF stimulation by DELFIA assay	ic50	0.0009	uM
N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]prop-2-enamide	1364464: Inhibition of EGFR L858R mutant phosphorylation in human H3255 cells preincubated for 2 hrs followed by EGF stimulation for 10 mins by sandwich ELISA	ic50	0.0010	uM
N-[4-[2-(dimethylamino)ethoxy]phenyl]-8-(4-fluorophenyl)sulfanyl-9-(oxan-4-yl)purin-2-amine	1391282: Inhibition of EGFR L858R mutant (unknown origin) using poly (Glu, Tyr) as substrate after 40 mins by kinase-glo plus luminescence assay	ic50	0.0012	uM
1-[3-(4-amino-7-cyclopentylpyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl]-3-(2,4-dichlorophenyl)urea	748805: Inhibition of human EGFR extracellular domain/TIE2 intracellular domain transfected in mouse NIH/3T3 cells assessed as phosphotyrosine level preincubated for 60 mins followed by EGF stimulation by DELFIA assay	ic50	0.0012	uM
N-[4-[2-(dimethylamino)ethoxy]phenyl]-9-(oxan-4-yl)-8-phenylsulfanylpurin-2-amine	1391282: Inhibition of EGFR L858R mutant (unknown origin) using poly (Glu, Tyr) as substrate after 40 mins by kinase-glo plus luminescence assay	ic50	0.0017	uM
N-[4-[4-(dimethylamino)piperidin-1-yl]phenyl]-9-(oxan-4-yl)-8-phenylsulfanylpurin-2-amine	1391282: Inhibition of EGFR L858R mutant (unknown origin) using poly (Glu, Tyr) as substrate after 40 mins by kinase-glo plus luminescence assay	ic50	0.0019	uM
6-[4-[(4-ethylpiperazin-1-yl)methyl]phenyl]-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine	710623: Inhibition of EGFR2	ic50	0.0020	uM
N-[(3R,4R)-4-fluoro-1-[6-[(3-methoxy-1-methylpyrazol-4-yl)amino]-9-propan-2-ylpurin-2-yl]pyrrolidin-3-yl]prop-2-enamide	1364464: Inhibition of EGFR L858R mutant phosphorylation in human H3255 cells preincubated for 2 hrs followed by EGF stimulation for 10 mins by sandwich ELISA	ic50	0.0020	uM
N-[(3R,4R)-4-fluoro-1-[6-[(1-methylpyrazol-4-yl)amino]-9-propan-2-ylpurin-2-yl]pyrrolidin-3-yl]prop-2-enamide	1364464: Inhibition of EGFR L858R mutant phosphorylation in human H3255 cells preincubated for 2 hrs followed by EGF stimulation for 10 mins by sandwich ELISA	ic50	0.0020	uM
N-[4-(4-methylpiperazin-1-yl)phenyl]-9-(oxan-4-yl)-8-phenylsulfanylpurin-2-amine	1391282: Inhibition of EGFR L858R mutant (unknown origin) using poly (Glu, Tyr) as substrate after 40 mins by kinase-glo plus luminescence assay	ic50	0.0020	uM
Osimertinib	1391282: Inhibition of EGFR L858R mutant (unknown origin) using poly (Glu, Tyr) as substrate after 40 mins by kinase-glo plus luminescence assay	ic50	0.0021	uM
4-[2-[4-(4-methylpiperazin-1-yl)anilino]-8-phenylsulfanylpurin-9-yl]cyclohexan-1-ol	1391282: Inhibition of EGFR L858R mutant (unknown origin) using poly (Glu, Tyr) as substrate after 40 mins by kinase-glo plus luminescence assay	ic50	0.0024	uM
8-(benzenesulfinyl)-N-[4-[2-(dimethylamino)ethoxy]phenyl]-9-(oxan-4-yl)purin-2-amine	1391282: Inhibition of EGFR L858R mutant (unknown origin) using poly (Glu, Tyr) as substrate after 40 mins by kinase-glo plus luminescence assay	ic50	0.0026	uM
7-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]-3-phenyl-1-[(3S)-1-prop-2-enoylpyrrolidin-3-yl]-4H-pyrimido[4,5-d]pyrimidin-2-one	1053594: Inhibition of EGFR L851Q mutant (unknown origin)	ic50	0.0030	uM
Mobocertinib	1935456: Inhibition of mouse EGFR L858R mutant stably expressed in mouse BaF3 cells assessed as cell viability incubated for 3 days by Cell Titer-Glo assay	ic50	0.0033	uM
2-[4-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-N-methylacetamide	1545491: Inhibition of human HER3 expressed in baculovirus/Sf21 system by ELISA	ic50	0.0040	uM
N-[(3R,4R)-4-fluoro-1-[6-[(3-methoxy-1-methylpyrazol-4-yl)amino]-9-methylpurin-2-yl]pyrrolidin-3-yl]prop-2-enamide	1364464: Inhibition of EGFR L858R mutant phosphorylation in human H3255 cells preincubated for 2 hrs followed by EGF stimulation for 10 mins by sandwich ELISA	ic50	0.0040	uM
8-(benzenesulfinyl)-9-cyclopentyl-N-[4-(4-methylpiperazin-1-yl)phenyl]purin-2-amine	1391282: Inhibition of EGFR L858R mutant (unknown origin) using poly (Glu, Tyr) as substrate after 40 mins by kinase-glo plus luminescence assay	ic50	0.0042	uM
9-cyclopentyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-8-phenylsulfanylpurin-2-amine	1391282: Inhibition of EGFR L858R mutant (unknown origin) using poly (Glu, Tyr) as substrate after 40 mins by kinase-glo plus luminescence assay	ic50	0.0042	uM
1-[3-(4-amino-7-cyclopentylpyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl]-3-(4-chlorophenyl)urea	748805: Inhibition of human EGFR extracellular domain/TIE2 intracellular domain transfected in mouse NIH/3T3 cells assessed as phosphotyrosine level preincubated for 60 mins followed by EGF stimulation by DELFIA assay	ic50	0.0046	uM
2-[2-[4-[3-chloro-4-(3-chlorophenoxy)anilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy]ethanol	632227: Inhibition of human N-terminus peptide (DYKDDDD)-tagged EGFR expressed in baculovirus infected insect cells using [gamma-32P]ATP as substrate after 60 mins by scintillation counting	ic50	0.0057	uM
N-[4-[2-(dimethylamino)ethoxy]phenyl]-8-(3-fluorophenyl)sulfanyl-9-(oxan-4-yl)purin-2-amine	1391282: Inhibition of EGFR L858R mutant (unknown origin) using poly (Glu, Tyr) as substrate after 40 mins by kinase-glo plus luminescence assay	ic50	0.0058	uM
N-[2-[4-[3-chloro-4-[3-(trifluoromethyl)phenoxy]anilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]-3-hydroxypropanamide;methanesulfonic acid	632227: Inhibition of human N-terminus peptide (DYKDDDD)-tagged EGFR expressed in baculovirus infected insect cells using [gamma-32P]ATP as substrate after 60 mins by scintillation counting	ic50	0.0072	uM
N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine	632227: Inhibition of human N-terminus peptide (DYKDDDD)-tagged EGFR expressed in baculovirus infected insect cells using [gamma-32P]ATP as substrate after 60 mins by scintillation counting	ic50	0.0077	uM
Neratinib	624851: Binding constant for ERBB3 kinase domain	kd	0.0077	uM
N-[(3R,4R)-1-[6-[(1,3-dimethylpyrazol-4-yl)amino]-9-propan-2-ylpurin-2-yl]-4-fluoropyrrolidin-3-yl]prop-2-enamide	1364464: Inhibition of EGFR L858R mutant phosphorylation in human H3255 cells preincubated for 2 hrs followed by EGF stimulation for 10 mins by sandwich ELISA	ic50	0.0090	uM
N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5-methylpyrrolo[3,2-d]pyrimidin-4-amine	632227: Inhibition of human N-terminus peptide (DYKDDDD)-tagged EGFR expressed in baculovirus infected insect cells using [gamma-32P]ATP as substrate after 60 mins by scintillation counting	ic50	0.0092	uM
2-[4-[3-chloro-4-(3-chlorophenoxy)anilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethanol	632227: Inhibition of human N-terminus peptide (DYKDDDD)-tagged EGFR expressed in baculovirus infected insect cells using [gamma-32P]ATP as substrate after 60 mins by scintillation counting	ic50	0.0095	uM
Erlotinib	1364464: Inhibition of EGFR L858R mutant phosphorylation in human H3255 cells preincubated for 2 hrs followed by EGF stimulation for 10 mins by sandwich ELISA	ic50	0.0100	uM
N-[2-[4-[3-chloro-4-[3-(trifluoromethyl)phenoxy]anilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]-2-hydroxyacetamide	632227: Inhibition of human N-terminus peptide (DYKDDDD)-tagged EGFR expressed in baculovirus infected insect cells using [gamma-32P]ATP as substrate after 60 mins by scintillation counting	ic50	0.0100	uM
N-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide;dihydrochloride	2158840: Inhibition of erbB3 in human MDA-MB-453 cells assessed as reduction in heregulin-stimulated tyrosine phosphorylation	ic50	0.0140	uM
2-[2-[4-[3-chloro-4-[3-(trifluoromethyl)phenoxy]anilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy]ethanol	632227: Inhibition of human N-terminus peptide (DYKDDDD)-tagged EGFR expressed in baculovirus infected insect cells using [gamma-32P]ATP as substrate after 60 mins by scintillation counting	ic50	0.0150	uM
N-[2-[4-[3-chloro-4-[3-(trifluoromethyl)phenoxy]anilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]-2-hydroxy-N-methylacetamide	632227: Inhibition of human N-terminus peptide (DYKDDDD)-tagged EGFR expressed in baculovirus infected insect cells using [gamma-32P]ATP as substrate after 60 mins by scintillation counting	ic50	0.0150	uM
4-N-(2,5-dimethoxyphenyl)-6-N-(3-methoxyphenyl)pyrimidine-4,6-diamine	1420637: Inhibition of recombinant human GST-tagged EGFR L858R mutant cytoplasmic domain expressed in baculovirus expression system using FAM-labeled peptide as substrate after 10 mins by mobility shift assay	ic50	0.0180	uM
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide;hydrate	624851: Binding constant for ERBB3 kinase domain	kd	0.0180	uM
N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine	632227: Inhibition of human N-terminus peptide (DYKDDDD)-tagged EGFR expressed in baculovirus infected insect cells using [gamma-32P]ATP as substrate after 60 mins by scintillation counting	ic50	0.0180	uM
N-[3-chloro-4-(3-methylphenoxy)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine	632227: Inhibition of human N-terminus peptide (DYKDDDD)-tagged EGFR expressed in baculovirus infected insect cells using [gamma-32P]ATP as substrate after 60 mins by scintillation counting	ic50	0.0200	uM
5-[[6-(3-chloroanilino)pyrimidin-4-yl]amino]-5-oxopentanoic acid	1420637: Inhibition of recombinant human GST-tagged EGFR L858R mutant cytoplasmic domain expressed in baculovirus expression system using FAM-labeled peptide as substrate after 10 mins by mobility shift assay	ic50	0.0210	uM
1-[(3R,4R)-3-[[5-chloro-2-[(1-methylpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxymethyl]-4-methoxypyrrolidin-1-yl]prop-2-en-1-one	1364464: Inhibition of EGFR L858R mutant phosphorylation in human H3255 cells preincubated for 2 hrs followed by EGF stimulation for 10 mins by sandwich ELISA	ic50	0.0210	uM
2-[2-[4-[3-chloro-4-[3-(trifluoromethyl)phenoxy]anilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethylamino]ethanol	632227: Inhibition of human N-terminus peptide (DYKDDDD)-tagged EGFR expressed in baculovirus infected insect cells using [gamma-32P]ATP as substrate after 60 mins by scintillation counting	ic50	0.0220	uM
N-[2-[4-[3-chloro-4-[3-(trifluoromethyl)phenoxy]anilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]-3-hydroxy-3-methylbutanamide	632227: Inhibition of human N-terminus peptide (DYKDDDD)-tagged EGFR expressed in baculovirus infected insect cells using [gamma-32P]ATP as substrate after 60 mins by scintillation counting	ic50	0.0230	uM
N-[5-[1-[4-(4-acetylpiperazin-1-yl)cyclohexyl]-4-aminopyrazolo[3,4-d]pyrimidin-3-yl]-2-phenoxyphenyl]prop-2-enamide	1939980: Inhibition of HER3 (unknown origin)	ic50	0.0230	uM
5-[(6-morpholin-4-ylpyrimidin-4-yl)amino]-5-oxopentanoic acid	1420637: Inhibition of recombinant human GST-tagged EGFR L858R mutant cytoplasmic domain expressed in baculovirus expression system using FAM-labeled peptide as substrate after 10 mins by mobility shift assay	ic50	0.0270	uM
N-[3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl]-5-methylpyrrolo[3,2-d]pyrimidin-4-amine	632227: Inhibition of human N-terminus peptide (DYKDDDD)-tagged EGFR expressed in baculovirus infected insect cells using [gamma-32P]ATP as substrate after 60 mins by scintillation counting	ic50	0.0270	uM
N-[3-chloro-4-(2-chlorophenoxy)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine	632227: Inhibition of human N-terminus peptide (DYKDDDD)-tagged EGFR expressed in baculovirus infected insect cells using [gamma-32P]ATP as substrate after 60 mins by scintillation counting	ic50	0.0270	uM
5-[[6-(3-methoxyanilino)pyrimidin-4-yl]amino]-5-oxopentanoic acid	1420637: Inhibition of recombinant human GST-tagged EGFR L858R mutant cytoplasmic domain expressed in baculovirus expression system using FAM-labeled peptide as substrate after 10 mins by mobility shift assay	ic50	0.0310	uM
2-[2-[4-[3-chloro-4-[3-(trifluoromethyl)phenoxy]anilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethylsulfinyl]ethanol	632227: Inhibition of human N-terminus peptide (DYKDDDD)-tagged EGFR expressed in baculovirus infected insect cells using [gamma-32P]ATP as substrate after 60 mins by scintillation counting	ic50	0.0310	uM
N-[4-[4-amino-1-[4-(4-methylpiperazin-1-yl)cyclohexyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]-7-chloro-1,3-benzoxazol-2-amine	517320: Inhibition of EGFR L858 mutant	ic50	0.0315	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases expression, affects cotreatment	9
Estradiol	decreases expression, increases reaction, affects expression, affects cotreatment	6
sodium arsenite	affects cotreatment, decreases expression, increases abundance	5
Doxorubicin	affects response to substance, decreases phosphorylation, decreases reaction, decreases expression	5
trichostatin A	affects cotreatment, increases expression, affects expression	4
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases response to substance, increases expression, increases phosphorylation, affects reaction, decreases response to substance (+1 more)	4
Air Pollutants	decreases methylation, increases expression, decreases expression, increases abundance	4
Quercetin	decreases reaction, increases phosphorylation, decreases expression, decreases phosphorylation	4
Tetrachlorodibenzodioxin	decreases expression, increases expression	4
Particulate Matter	decreases expression, increases abundance, decreases methylation, increases expression	4
bisphenol A	affects methylation, decreases expression, increases expression	3
Curcumin	decreases expression, decreases activity, decreases phosphorylation, increases reaction	3
Etoposide	affects response to substance, decreases expression	3
Cyclosporine	decreases expression	3
Aflatoxin B1	affects expression, decreases expression, increases methylation	3
entinostat	affects cotreatment, increases expression	2
Fulvestrant	decreases reaction, increases expression, increases phosphorylation, decreases expression	2
Vorinostat	affects cotreatment, increases expression	2
Lapatinib	decreases activity, decreases expression	2
Panobinostat	affects cotreatment, increases expression	2
Arsenic	decreases expression, increases abundance, affects cotreatment	2
Benzo(a)pyrene	decreases expression	2
Daunorubicin	decreases expression	2
Mitoxantrone	decreases expression	2
Silver	decreases expression	2
FR900359	affects phosphorylation	1
triphenyl(phenylethynyl)phosphonium	decreases expression	1
uranyl acetate	affects expression	1
lead acetate	affects cotreatment, decreases expression	1
sodium arsenate	decreases expression, increases abundance	1

ChEMBL screening assays

169 unique, capped per target: 169 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1034137	Binding	Inhibition of EGFR E746-A750del mutant at 3 uM	Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors. — J Med Chem

Cellosaurus cell lines

31 cell lines: 25 cancer cell line, 5 spontaneously immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1184	DV-90	Cancer cell line	Male
CVCL_1406	MFE-296	Cancer cell line	Female
CVCL_1603	NCI-N87	Cancer cell line	Male
CVCL_2112	MFE-319	Cancer cell line	Female
CVCL_B8FG	Abcam HCT 116 ERBB3 KO	Cancer cell line	Male
CVCL_B8VC	Abcam MCF-7 ERBB3 KO	Cancer cell line	Female
CVCL_B9HP	Abcam A-549 ERBB3 KO	Cancer cell line	Male
CVCL_C9DN	NCI-N87/Cas9-hyg	Cancer cell line	Male
CVCL_D2TC	CHO/HER3-PA	Spontaneously immortalized cell line	Female
CVCL_D2TD	CHO/PA16-HER3	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery