ERBB2

Summary

ERBB2 (erb-b2 receptor tyrosine kinase 2, HGNC:3430) is a protein-coding gene on chromosome 17q12, encoding Receptor tyrosine-protein kinase erbB-2 (P04626). Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. In precision oncology, ERBB2 Amplification confers sensitivity to Trastuzumab + Neratinib in Her2-receptor Positive Breast Cancer (CIViC Level A); 182 further curated variant–drug associations are listed below. It is a selective cancer dependency (DepMap: 17.7% of cell lines).

This gene encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. This protein has no ligand binding domain of its own and therefore cannot bind growth factors. However, it does bind tightly to other ligand-bound EGF receptor family members to form a heterodimer, stabilizing ligand binding and enhancing kinase-mediated activation of downstream signalling pathways, such as those involving mitogen-activated protein kinase and phosphatidylinositol-3 kinase. Allelic variations at amino acid positions 654 and 655 of isoform a (positions 624 and 625 of isoform b) have been reported, with the most common allele, Ile654/Ile655, shown here. Amplification and/or overexpression of this gene has been reported in numerous cancers, including breast and ovarian tumors. Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized.

Source: NCBI Gene 2064 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Hirschsprung disease (Supportive, GenCC) — +3 more curated relationships
• GWAS associations: 17
• Clinical variants (ClinVar): 830 total — 15 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 49
• Druggable target: yes — 83 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 183 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 16 cancer types
• Cancer dependency (DepMap): dependent in 17.7% of screened cell lines
• MANE Select transcript: NM_004448

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3430
Approved symbol	ERBB2
Name	erb-b2 receptor tyrosine kinase 2
Location	17q12
Locus type	gene with protein product
Status	Approved
Aliases	NEU, HER-2, CD340, HER2, c-ERB2, c-ERB-2, MLN-19, p185(erbB2)
Ensembl gene	ENSG00000141736
Ensembl biotype	protein_coding
OMIM	164870
Entrez	2064

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 24 protein_coding, 6 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000269571, ENST00000445658, ENST00000578199, ENST00000578373, ENST00000578502, ENST00000578630, ENST00000578709, ENST00000580074, ENST00000582648, ENST00000582788, ENST00000582818, ENST00000583038, ENST00000583391, ENST00000584014, ENST00000584099, ENST00000584450, ENST00000584601, ENST00000584684, ENST00000584888, ENST00000584908, ENST00000863095, ENST00000863096, ENST00000863097, ENST00000863098, ENST00000863099, ENST00000863100, ENST00000863101, ENST00000863102, ENST00000863103, ENST00000938923, ENST00000938924, ENST00000938925, ENST00000959774, ENST00000959775

RefSeq mRNA: 30 — MANE Select: NM_004448 NM_001005862, NM_001289936, NM_001289937, NM_001289938, NM_001382782, NM_001382783, NM_001382784, NM_001382785, NM_001382786, NM_001382787, NM_001382788, NM_001382789, NM_001382790, NM_001382791, NM_001382792, NM_001382793, NM_001382794, NM_001382795, NM_001382796, NM_001382797, NM_001382798, NM_001382799, NM_001382800, NM_001382801, NM_001382802, NM_001382803, NM_001382804, NM_001382805, NM_001382806, NM_004448

CCDS: CCDS32642, CCDS45667, CCDS77016, CCDS77017, CCDS92296

Canonical transcript exons

ENST00000269571 — 27 exons

Exon	Start	End
ENSE00003465438	39726562	39726659
ENSE00003474439	39706990	39707141
ENSE00003523294	39715446	39715536
ENSE00003528993	39727295	39727547
ENSE00003530664	39715286	39715359
ENSE00003564965	39716301	39716433
ENSE00003572793	39711928	39712047
ENSE00003580476	39725327	39725402
ENSE00003585058	39726815	39727003
ENSE00003591380	39723319	39723457
ENSE00003605099	39710086	39710201
ENSE00003610105	39712322	39712448
ENSE00003625564	39715740	39715939
ENSE00003625600	39724726	39724911
ENSE00003629275	39723912	39724010
ENSE00003629888	39719787	39719834
ENSE00003632167	39717320	39717480
ENSE00003648452	39709318	39709452
ENSE00003650103	39725707	39725853
ENSE00003653182	39708321	39708534
ENSE00003655754	39723538	39723660
ENSE00003657083	39725049	39725204
ENSE00003663782	39709813	39709881
ENSE00003675634	39716515	39716605
ENSE00003679402	39710340	39710481
ENSE00003907546	39727689	39728658
ENSE00003909903	39700064	39700311

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 97.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.8860 / max 788.7767, expressed in 1672 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160623	9.9827	1303
160622	6.3473	1311
160621	3.9997	1212
160618	3.4329	1436
160619	0.5707	289
160620	0.2726	130
160626	0.1540	36
160627	0.1030	31
160624	0.0134	1
160625	0.0097	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	97.71	gold quality
right uterine tube	UBERON:0001302	97.26	gold quality
sural nerve	UBERON:0015488	96.73	gold quality
skin of leg	UBERON:0001511	96.65	gold quality
esophagus mucosa	UBERON:0002469	96.57	gold quality
metanephros cortex	UBERON:0010533	96.57	gold quality
skin of abdomen	UBERON:0001416	96.50	gold quality
nerve	UBERON:0001021	96.39	gold quality
tibial nerve	UBERON:0001323	96.39	gold quality
renal medulla	UBERON:0000362	96.35	gold quality
minor salivary gland	UBERON:0001830	96.10	gold quality
right lobe of thyroid gland	UBERON:0001119	96.09	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.02	gold quality
mucosa of transverse colon	UBERON:0004991	95.99	gold quality
left lobe of thyroid gland	UBERON:0001120	95.86	gold quality
zone of skin	UBERON:0000014	95.48	gold quality
descending thoracic aorta	UBERON:0002345	95.36	gold quality
thyroid gland	UBERON:0002046	95.30	gold quality
mouth mucosa	UBERON:0003729	95.08	gold quality
right atrium auricular region	UBERON:0006631	94.99	gold quality
saliva-secreting gland	UBERON:0001044	94.76	gold quality
transverse colon	UBERON:0001157	94.60	gold quality
rectum	UBERON:0001052	94.58	gold quality
thoracic aorta	UBERON:0001515	94.55	gold quality
ascending aorta	UBERON:0001496	94.45	gold quality
ventricular zone	UBERON:0003053	94.34	gold quality
adult mammalian kidney	UBERON:0000082	94.22	gold quality
aorta	UBERON:0000947	93.98	gold quality
epithelium of bronchus	UBERON:0002031	93.98	gold quality
apex of heart	UBERON:0002098	93.96	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-10018	yes	159.22
E-MTAB-6678	yes	16.32
E-ANND-3	yes	9.97
E-CURD-112	yes	4.23
E-CURD-53	no	2882.67

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
MSI1	Activation
NOTCH3	Activation

Upstream regulators (CollecTRI, top): AR, ATF1, ATF4, ATF7, CREB1, DENND4A, DTX1, EGR2, ELF1, ELF3, ELK1, ENO1, EP300, ESR1, ESR2, ETS1, ETS2, ETV1, ETV4, FOXM1, FOXN1, FOXP3, GABPA, GATA3, GATA4, GATA5, GLI3, HIF1A, HNF4A, HSF1, JUN, JUND, MYB, MYBL2, MYC, NCOA1, NCOA2, NCOA3, NFE2L2, NFKB

miRNA regulators (miRDB)

48 targeting ERBB2, 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-4533	100.00	69.48	2758
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 17.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• peptide library generation for HER2/neu ligand identification (PMID:11700053)
• HER-2 gene amplification and protein overexpression has been associated with increased risk of advanced-stage breast cancer and poor prognosis. (PMID:11731415)
• Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. (PMID:11751413)
• overexpression not associated with in vitro drug resistance to CMF or FEC chemotherapy combinations in primary breast cancer (PMID:11759828)
• Expression and gene copy number analysis of ERBB2 oncogene in prostate cancer. (PMID:11786427)
• Identification of a minimal c-erbB-2 promoter region that mediates preferential expression of a linked foreign gene in human breast cancer cells (PMID:11836576)
• NH(2)-terminal truncated HER-2 protein but not full-length receptor is associated with nodal metastasis in human breast cancer (PMID:11839648)
• HER-2-positive breast carcinomas as a particular subset with peculiar clinical behaviors. (PMID:11839672)
• Characterization of the HER-2/neu oncogene by immunohistochemical and fluorescence in situ hybridization analysis in oral and oropharyngeal squamous cell carcinoma (PMID:11839675)
• Automated electrorotation to reveal dielectric variations related to HER-2/neu overexpression in MCF-7 sublines (PMID:11839684)
• ErbB-2 demonstrates a strong tendency toward stable self-association of transmembrane domains identifiable as coexisting populations of peptides whose associations are thought to modulate signal transduction. (PMID:11841227)
• lack of amplification in nasopharyngeal neoplasms (PMID:11850071)
• feasibility of fluorescence in situ hybridization analysis of HER-2/neu amplification in oral mucosa brushings and to compare the HER-2/neu status with the history and smoking and drinking habits of healthy subjects (PMID:11850076)
• Data suggest that amplification of Her-2/neu appears to be mainly involved in initiation of breast oncogenesis and that its role in progression of breast cancers is uncertain. (PMID:11850540)
• Except in a certain subset of cases, aneusomy 17 probably is not a significant factor for HER-2/neu protein expression or for clinical assessment of HER-2/neu status. (PMID:11850542)
• Bombesin antagonists inhibit growth of MDA-MB-435 estrogen-independent breast cancers and decrease the expression of the ErbB-2/HER-2 oncoprotein and c-jun and c-fos oncogenes (PMID:11891317)
• Increased c-erbB-2 expression contributes to the development of cholangiocarcinogenesis into an advanced stage associated with tumour metastasis. (PMID:11895493)
• expression of cyclooxygenase 2 in HE-2 positive breast cancer (PMID:11901151)
• Epidermal growth factor contains both positive and negative determinants for interaction with ErbB-2/ErbB-3 heterodimers (PMID:11914075)
• expression correlated with increased event-free and overall survival in high-grade osteosarcoma (PMID:11920494)
• ErbB-beta-catenin complexes are associated with human infiltrating ductal breast and murine mammary tumor virus (MMTV)-Wnt-1 and MMTV-c-Neu transgenic carcinomas. (PMID:11950845)
• p53 mutational pathway may favor selection for ErbB2 gene amplification during tumor progression in breast cancer (PMID:11953857)
• Mechanism of 17-beta-estradiol-induced Erk1/2 activation in breast cancer cells. A role for HER2 AND PKC-delta (PMID:11960991)
• Cyclooxygenase-2 (COX-2), epidermal growth factor receptor (EGFR), and Her-2/neu are expressed in ovarian cancer. (PMID:11972392)
• gene is essential in preventing dilated cardiomyopathy (PMID:11984589)
• overexpression seen in 16% of NSCLC tumors, most frequently in adenocarcinomas and large cell carcinomas (PMID:11986780)
• identification of a dimerization motif for ErbB homomeric association (PMID:12000754)
• ErbB2 activation of ESX gene expression (PMID:12032832)
• ErbB2 membrane RTK can confer resistance to taxol-induced apoptosis by directly phosphorylating Cdc2. (PMID:12049736)
• HER-2/neu peptides can activate T cells in draining lymph nodes from women with invasive breast cancer. (PMID:12060497)
• S-erbB-2 serum levels above 40 U/ml independently predicted unfavorable response to 2d-line hormone or chemotherapy in advanced metastatic breast cancer. 1st-line drugs may select for overexpression of erbB-2 genes and lesser response to 2d-line drugs. (PMID:12065844)
• Expression of c-erbB-2 in node negative breast cancer does not correlate with estrogen receptor status, predictors of hormone responsiveness, or PCNA expression (PMID:12088102)
• Role of the N-terminus of epidermal growth factor in binding studied by phage display. (PMID:12093292)
• Her-2/neu expression and gene amplification in gastrinomas is correlated with tumor biology, growth, and aggressiveness. (PMID:12097278)
• Overexpression of erbb2 increases expression of VEGF A, C and D in breast carcinoma (PMID:12115372)
• the expression of mitochondria-encoded COXII is HRG-responsive. The levels of ErbB2 expression are decisive for the diverse biological activities of HRG. (PMID:12115729)
• ERBB2 binds to the SH2 domain of CHK and inhibits cell growth in human breast tumor cell lines (PMID:12122014)
• The expression of this molecule and its correlation with prognostic markers in patients with head and neck tumors (PMID:12127695)
• ErbB1 and ErbB2 employ different mechanisms of plasma membrane targeting during keratinocyte differentiation; cytoskeletal association may facilitate the coupling of activated ErbB1 and ERK. (PMID:12135609)
• ERBB-2 overexpression and cyclooxygenase-2 up-regulation in human cholangiocarcinoma and risk conditions. (PMID:12143054)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	erbb2	ENSDARG00000026294
mus_musculus	Erbb2	ENSMUSG00000062312
rattus_norvegicus	Erbb2	ENSRNOG00000006450

Paralogs (53): INSRR (ENSG00000027644), MUSK (ENSG00000030304), FLT4 (ENSG00000037280), EPHA3 (ENSG00000044524), ROS1 (ENSG00000047936), LTK (ENSG00000062524), ERBB3 (ENSG00000065361), 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), 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-2 — P04626 (reviewed: P04626)

Alternative names: Metastatic lymph node gene 19 protein, Proto-oncogene Neu, Proto-oncogene c-ErbB-2, Tyrosine kinase-type cell surface receptor HER2, p185erbB2

All UniProt accessions (11): B4DTR1, P04626, F5H1T4, J3KRI9, J3KTI5, J3QL83, J3QLU9, J3QLV2, J3QRJ7, J3QRX1, X5DNK3

UniProt curated annotations — full annotation on UniProt →

Function. Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-RHOA-DIAPH1 signaling pathway elicits the phosphorylation and thus the inhibition of GSK3B at cell membrane. This prevents the phosphorylation of APC and CLASP2, allowing its association with the cell membrane. In turn, membrane-bound APC allows the localization of MACF1 to the cell membrane, which is required for microtubule capture and stabilization. In the nucleus is involved in transcriptional regulation. Associates with the 5’-TCAAATTC-3’ sequence in the PTGS2/COX-2 promoter and activates its transcription. Implicated in transcriptional activation of CDKN1A; the function involves STAT3 and SRC. Involved in the transcription of rRNA genes by RNA Pol I and enhances protein synthesis and cell growth.

Subunit / interactions. Homodimer. Heterodimer with EGFR, ERBB3 and ERBB4. Part of a complex with EGFR and either PIK3C2A or PIK3C2B. May interact with PIK3C2B when phosphorylated on Tyr-1196. Interacts with PLXNB1. Interacts (when phosphorylated on Tyr-1248) with MEMO1. Interacts with MUC1; the interaction is enhanced by heregulin (HRG). Interacts (when phosphorylated on Tyr-1139) with GRB7 (via SH2 domain). Interacts (when phosphorylated on Tyr-1248) with ERBIN. Interacts with KPNB1, RANBP2, EEA1, CRM1 and CLTC. Interacts with PTK6. Interacts with RPA194 and ACTB. Interacts with PRKCABP, SRC and MYOC. Interacts (preferentially with the tyrosine phosphorylated form) with CPNE3; this interaction occurs at the cell membrane and is increased in a growth factor heregulin-dependent manner. Interacts with HSP90AA1 and HSP90AB1 in an ATP-dependent manner; the interaction suppresses ERBB2 kinase activity. Interacts with SORL1; this interaction regulates ERBB2 subcellular distribution by promoting its recycling after internalization from endosomes back to the plasma membrane, hence stimulates ERBB2-mediated signaling. Interacts with SH3BGRL. Interacts with ROR1.

Subcellular location. Cell membrane. Cell projection. Ruffle membrane Cell membrane. Early endosome. Cytoplasm. Perinuclear region. Nucleus Cytoplasm. Nucleus.

Tissue specificity. Expressed in a variety of tumor tissues including primary breast tumors and tumors from small bowel, esophagus, kidney and mouth.

Post-translational modifications. Autophosphorylated. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Ligand-binding increases phosphorylation on tyrosine residues. Signaling via SEMA4C promotes phosphorylation at Tyr-1248. Dephosphorylated by PTPN12.

Disease relevance. Glioma (GLM) [MIM:137800] Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. The gene represented in this entry is involved in disease pathogenesis. Ovarian cancer (OC) [MIM:167000] The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. The gene represented in this entry is involved in disease pathogenesis. Lung cancer (LNCR) [MIM:211980] A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. The gene represented in this entry is involved in disease pathogenesis. Gastric cancer (GASC) [MIM:613659] A malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions, resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease. The protein represented in this entry is involved in disease pathogenesis. Chromosomal aberrations involving ERBB2 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with CDK12, leading to CDK12-ERBB2 fusion leading to truncated CDK12 protein not in-frame with ERBB2. Visceral neuropathy, familial, 2, autosomal recessive (VSCN2) [MIM:619465] An autosomal recessive disorder characterized by intestinal dysmotility due to aganglionosis (Hirschsprung disease), hypoganglionosis, and/or chronic intestinal pseudoobstruction. Patients also show peripheral axonal neuropathy, hypotonia, mild developmental delay, unilateral ptosis, and sensorineural hearing loss. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by dimerization. Not activated by EGF, TGF-alpha and amphiregulin. Interaction with PTK6 increases its intrinsic kinase activity.

Polymorphism. There are four alleles due to the variations in positions 654 and 655. Allele B1 (Ile-654/Ile-655) has a frequency of 0.782; allele B2 (Ile-654/Val-655) has a frequency of 0.206; allele B3 (Val-654/Val-655) has a frequency of 0.012.

Miscellaneous. Produced by alternative initiation at Met-611 of isoform 1. Produced by alternative initiation at Met-687 of isoform 1. Produced by alternative splicing of isoform 1.

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

Isoforms (6)

UniProt ID	Names	Canonical?
P04626-1	1, ERBB2, HER2	yes
P04626-2	2, CTF-611
P04626-3	3, CTF-687
P04626-4	4
P04626-5	5
P04626-6	6, B

RefSeq proteins (30): NP_001005862, NP_001276865, NP_001276866, NP_001276867, NP_001369711, NP_001369712, NP_001369713, NP_001369714, NP_001369715, NP_001369716, NP_001369717, NP_001369718, NP_001369719, NP_001369720, NP_001369721, NP_001369722, NP_001369723, NP_001369724, NP_001369725, NP_001369726, NP_001369727, NP_001369728, NP_001369729, NP_001369730, NP_001369731, NP_001369732, NP_001369733, NP_001369734, NP_001369735, NP_004439* (*=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
IPR008266	Tyr_kinase_AS	Active_site
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR016245	Tyr_kinase_EGF/ERB/XmrK_rcpt	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR032778	GF_recep_IV	Domain
IPR036941	Rcpt_L-dom_sf	Homologous_superfamily
IPR049328	TM_ErbB1	Domain
IPR050122	RTK	Family

Pfam: PF00757, PF01030, PF07714, PF14843, PF21314

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 (198 total): strand 60, helix 43, disulfide bond 25, sequence variant 13, modified residue 12, turn 11, glycosylation site 7, splice variant 7, mutagenesis site 5, region of interest 4, binding site 2, topological domain 2, signal peptide 1, chain 1, short sequence motif 1, compositionally biased region 1, active site 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

63 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
1MFG	X-RAY DIFFRACTION	1.25
8VB5	X-RAY DIFFRACTION	1.48
8JYR	X-RAY DIFFRACTION	1.69
8U8X	X-RAY DIFFRACTION	1.69
8JYQ	X-RAY DIFFRACTION	1.75
7PCD	X-RAY DIFFRACTION	1.77
5TQS	X-RAY DIFFRACTION	1.88
1MFL	X-RAY DIFFRACTION	1.88
4GFU	X-RAY DIFFRACTION	2
6LBX	X-RAY DIFFRACTION	2.03
9IUT	X-RAY DIFFRACTION	2.09
5MY6	X-RAY DIFFRACTION	2.25
3PP0	X-RAY DIFFRACTION	2.25
1QR1	X-RAY DIFFRACTION	2.4
3H3B	X-RAY DIFFRACTION	2.45
2A91	X-RAY DIFFRACTION	2.5
4NND	X-RAY DIFFRACTION	2.5
1N8Z	X-RAY DIFFRACTION	2.52
4HRL	X-RAY DIFFRACTION	2.55
8VQD	ELECTRON MICROSCOPY	2.61
4HRN	X-RAY DIFFRACTION	2.65
9MTE	ELECTRON MICROSCOPY	2.66
8VQE	ELECTRON MICROSCOPY	2.67
6BGT	X-RAY DIFFRACTION	2.7
3BE1	X-RAY DIFFRACTION	2.9
3MZW	X-RAY DIFFRACTION	2.9
6J71	X-RAY DIFFRACTION	2.92
7MN5	ELECTRON MICROSCOPY	2.93
5O4G	X-RAY DIFFRACTION	3
9L1S	ELECTRON MICROSCOPY	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04626-F1	74.65	0.43

Antibody-complex structures (SAbDab): 24 — 1N8Z, 1S78, 3BE1, 3H3B, 3N85, 3WLW, 3WSQ, 5MY6, 5O4G, 6ATT, 6BGT, 6J71, 6OGE, 7MN8, 7QVK, 8JYQ, 8JYR, 8PWH, 8Q6J, 8VQD, 9IUT, 9L1S, 9MTE, 9MTX

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): 845 (proton acceptor)

Ligand- & substrate-binding residues (2): 726–734; 753

Post-translational modifications (12): 182, 877, 1054, 1078, 1083, 1107, 1112, 1139, 1151, 1166, 1196, 1248

Disulfide bonds (25): 26–53, 162–192, 195–204, 199–212, 220–227, 224–235, 236–244, 240–252, 255–264, 268–295, 299–311, 315–331, 334–338, 342–367, 475–504, 511–520, 515–528, 531–540, 544–560, 563–576 …

Glycosylation sites (7): 68, 124, 187, 259, 530, 571, 629

Mutagenesis-validated functional residues (5):

Position	Phenotype
317–318	reduces dimerization with erbb3.
611	prevents synthesis of isoform 2.
687	prevents synthesis of isoform 3.
706	no effect on isoform production.
712	no effect on isoform production.

Function

Pathways and Gene Ontology

Reactome pathways

33 pathways

ID	Pathway
R-HSA-1227986	Signaling by ERBB2
R-HSA-1250196	SHC1 events in ERBB2 signaling
R-HSA-1251932	PLCG1 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-1963640	GRB2 events in ERBB2 signaling
R-HSA-1963642	PI3K events in ERBB2 signaling
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-416572	Sema4D induced cell migration and growth-cone collapse
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-8866910	TFAP2 (AP-2) family regulates transcription of growth factors and their receptors
R-HSA-9634285	Constitutive Signaling by Overexpressed ERBB2
R-HSA-9652282	Drug-mediated inhibition of ERBB2 signaling
R-HSA-9664565	Signaling by ERBB2 KD Mutants
R-HSA-9665233	Resistance of ERBB2 KD mutants to trastuzumab
R-HSA-9665244	Resistance of ERBB2 KD mutants to sapitinib
R-HSA-9665245	Resistance of ERBB2 KD mutants to tesevatinib
R-HSA-9665246	Resistance of ERBB2 KD mutants to neratinib
R-HSA-9665247	Resistance of ERBB2 KD mutants to osimertinib
R-HSA-9665249	Resistance of ERBB2 KD mutants to afatinib
R-HSA-9665250	Resistance of ERBB2 KD mutants to AEE788
R-HSA-9665251	Resistance of ERBB2 KD mutants to lapatinib
R-HSA-9665348	Signaling by ERBB2 ECD mutants
R-HSA-9665686	Signaling by ERBB2 TMD/JMD mutants
R-HSA-9665737	Drug resistance in ERBB2 TMD/JMD mutants

MSigDB gene sets: 0 (showing top):

GO Biological Process (48): protein phosphorylation (GO:0006468), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), enzyme-linked receptor protein signaling pathway (GO:0007167), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), epidermal growth factor receptor signaling pathway (GO:0007173), heart development (GO:0007507), neuromuscular junction development (GO:0007528), motor neuron axon guidance (GO:0008045), cell population proliferation (GO:0008283), Schwann cell development (GO:0014044), peptidyl-tyrosine phosphorylation (GO:0018108), neuron differentiation (GO:0030182), positive regulation of cell growth (GO:0030307), regulation of microtubule-based process (GO:0032886), immature T cell proliferation in thymus (GO:0033080), negative regulation of immature T cell proliferation in thymus (GO:0033088), positive regulation of Rho protein signal transduction (GO:0035025), intracellular signal transduction (GO:0035556), ERBB2-ERBB3 signaling pathway (GO:0038133), ERBB2-EGFR signaling pathway (GO:0038134), ERBB2-ERBB4 signaling pathway (GO:0038135), wound healing (GO:0042060), myelination (GO:0042552), negative regulation of apoptotic process (GO:0043066), positive regulation of MAP kinase activity (GO:0043406), positive regulation of MAPK cascade (GO:0043410), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), positive regulation of translation (GO:0045727), regulation of angiogenesis (GO:0045765), positive regulation of cell adhesion (GO:0045785), positive regulation of transcription by RNA polymerase I (GO:0045943), oligodendrocyte differentiation (GO:0048709), positive regulation of epithelial cell proliferation (GO:0050679), regulation of ERK1 and ERK2 cascade (GO:0070372), cellular response to growth factor stimulus (GO:0071363), cellular response to epidermal growth factor stimulus (GO:0071364), semaphorin-plexin signaling pathway (GO:0071526), positive regulation of protein targeting to membrane (GO:0090314), neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0099645)

GO Molecular Function (17): RNA polymerase I core binding (GO:0001042), protein tyrosine kinase activity (GO:0004713), transmembrane receptor protein tyrosine kinase activity (GO:0004714), transmembrane signaling receptor activity (GO:0004888), signaling receptor binding (GO:0005102), ATP binding (GO:0005524), coreceptor activity (GO:0015026), receptor tyrosine kinase binding (GO:0030971), identical protein binding (GO:0042802), ErbB-3 class receptor binding (GO:0043125), protein heterodimerization activity (GO:0046982), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), growth factor binding (GO:0019838)

GO Cellular Component (23): semaphorin receptor complex (GO:0002116), nucleus (GO:0005634), nucleoplasm (GO:0005654), early endosome (GO:0005769), cytosol (GO:0005829), plasma membrane (GO:0005886), basal plasma membrane (GO:0009925), endosome membrane (GO:0010008), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), neuromuscular junction (GO:0031594), ruffle membrane (GO:0032587), ERBB3:ERBB2 complex (GO:0038143), presynaptic membrane (GO:0042734), myelin sheath (GO:0043209), signaling receptor complex (GO:0043235), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737), endosome (GO:0005768), endomembrane system (GO:0012505), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Signaling by ERBB2	9
Signaling by ERBB2 in Cancer	2
Signaling by Receptor Tyrosine Kinases	1
Intracellular signaling by second messengers	1
Downregulation of ERBB2 signaling	1
PI3K/AKT Signaling in Cancer	1
Sema4D in semaphorin signaling	1
MAPK1/MAPK3 signaling	1
Negative regulation of the PI3K/AKT network	1
Signaling by PTK6	1
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1
Drug resistance in ERBB2 KD mutants	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
protein binding	3
plasma membrane region	3
cellular process	2
regulation of cellular process	2
signal transduction	2
intracellular anatomical structure	2
signaling receptor activity	2
signaling receptor binding	2
endosome	2
cytoplasm	2
phosphorylation	1
protein modification process	1
cell communication	1
signaling	1
cellular response to stimulus	1
cell surface receptor signaling pathway	1
enzyme-linked receptor protein signaling pathway	1
ERBB signaling pathway	1
animal organ development	1
circulatory system development	1
synapse organization	1
axon guidance	1
Schwann cell differentiation	1
glial cell development	1
protein phosphorylation	1
peptidyl-tyrosine modification	1
cell differentiation	1
generation of neurons	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
microtubule-based process	1
T cell differentiation in thymus	1
immature T cell proliferation	1
immature T cell proliferation in thymus	1
regulation of immature T cell proliferation in thymus	1
negative regulation of T cell differentiation in thymus	1
negative regulation of immature T cell proliferation	1

Protein interactions and networks

STRING

7626 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERBB2	EGF	P01133	998
ERBB2	NRG1	P98202	998
ERBB2	GRB2	P29354	994
ERBB2	ERBIN	Q96RT1	993
ERBB2	MUC4	Q99102	993
ERBB2	CD44	P16070	992
ERBB2	SHC1	P29353	992
ERBB2	GRB7	Q14451	990
ERBB2	HSP90AA1	P07900	985
ERBB2	ERBB3	P21860	984
ERBB2	EGFR	P00533	983
ERBB2	HSP90AB1	P08238	983
ERBB2	ERBB4	Q15303	983
ERBB2	IGF1R	P08069	980
ERBB2	SRC	P12931	980

IntAct

820 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	EGFR	psi-mi:“MI:0914”(association)	0.950
ERBB2	EGFR	psi-mi:“MI:0915”(physical association)	0.950
EGFR	ERBB2	psi-mi:“MI:0915”(physical association)	0.950
ERBB2	ERBB2	psi-mi:“MI:0915”(physical association)	0.930
ERBB2	ERBB2	psi-mi:“MI:0407”(direct interaction)	0.930
ERBB2	GRB2	psi-mi:“MI:0915”(physical association)	0.920
ERBB2	HSP90AA1	psi-mi:“MI:0915”(physical association)	0.860
ERBB2	ERBB4	psi-mi:“MI:0915”(physical association)	0.820
SHC1	ERBB2	psi-mi:“MI:0915”(physical association)	0.820
HSP90AB1	ERBB2	psi-mi:“MI:0915”(physical association)	0.790
LRIG1	ERBB2	psi-mi:“MI:0915”(physical association)	0.750
LRIG1	ERBB2	psi-mi:“MI:0403”(colocalization)	0.750

BioGRID (1213): ERBB2 (Affinity Capture-Western), ERBB2 (Biochemical Activity), ERBB2 (Affinity Capture-RNA), ERBB2 (Biochemical Activity), ERBB2 (Affinity Capture-MS), ERBB2 (Affinity Capture-MS), ERBB2 (Affinity Capture-MS), ERBB2 (Affinity Capture-MS), ERBB2 (Affinity Capture-MS), ERBB2 (Affinity Capture-MS), CYP17A1 (Two-hybrid), ERRFI1 (Two-hybrid), GLCE (Two-hybrid), IL13RA2 (Two-hybrid), KLK5 (Two-hybrid)

ESM2 similar proteins: A4FV98, A6NKP2, A6QLY2, O18735, O43488, O75382, O75648, O77485, O77486, O88676, P04626, P23764, P25325, P34059, P52848, Q02353, Q0VD18, Q10836, Q10981, Q10982, Q28113, Q32KH5, Q32KJ6, Q3U129, Q3UHN9, Q4R766, Q571E4, Q5I0D5, Q5RB73, Q5RJL2, Q6AYT7, Q6P988, Q7RTV5, Q7Z4H8, Q8CIW5, Q8K093, Q8N2K0, Q8WNQ7, Q96AZ1, Q96SL4

Diamond homologs: F1N9Y5, F1RDG9, G5EBZ8, G5EE56, O02466, O18735, O45539, O54967, P00519, P00520, P00521, P00522, P00525, P00526, P00528, P00533, P00534, P00535, P03949, P04412, P04626, P06239, P06240, P06494, P07948, P08103, P08630, P08631, P0CY46, P10447, P11273, P15209, P17713, P24786, P25911, P27446, P29317, P42679, P42680, P42681

SIGNOR signaling

98 interactions.

A	Effect	B	Mechanism
EGF	up-regulates	ERBB2	binding
EGFR	up-regulates	ERBB2	binding
ERBB2	up-regulates	GRB2	relocalization
ERBB2	up-regulates	ERBB2	phosphorylation
ERBB2	up-regulates	ESR1	phosphorylation
LRIG1	down-regulates	ERBB2	ubiquitination
DTX1	“up-regulates quantity by expression”	ERBB2	“transcriptional regulation”
NOTCH1	“up-regulates quantity by expression”	ERBB2	“transcriptional regulation”
ERBB2	up-regulates	SHC3	relocalization
ERBB2	up-regulates	EGFR	binding
sapitinib	down-regulates	ERBB2	“chemical inhibition”
ERBB2	“up-regulates quantity by expression”	MSI1	“transcriptional regulation”
ERBB2	“up-regulates quantity by expression”	NOTCH3	“transcriptional regulation”
lapatinib	down-regulates	ERBB2	“chemical inhibition”
ERBB2	up-regulates	DOCK7	phosphorylation
PRKACA	up-regulates	ERBB2	phosphorylation
6-{4-[(4-ethylpiperazin-1-yl)methyl]phenyl}-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine	down-regulates	ERBB2	“chemical inhibition”
afatinib	down-regulates	ERBB2	“chemical inhibition”
Arry-380	down-regulates	ERBB2	“chemical inhibition”
VARLITINIB	down-regulates	ERBB2	“chemical inhibition”
AV412	down-regulates	ERBB2	“chemical inhibition”
873837-23-1	down-regulates	ERBB2	“chemical inhibition”
canertinib	down-regulates	ERBB2	“chemical inhibition”
2-methoxy-N-[3-[4-[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]anilino]-6-quinazolinyl]prop-2-enyl]acetamide	down-regulates	ERBB2	“chemical inhibition”
CUDC-101	down-regulates	ERBB2	“chemical inhibition”
Mubritinib	down-regulates	ERBB2	“chemical inhibition”
neratinib	down-regulates	ERBB2	“chemical inhibition”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 154 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Constitutive Signaling by EGFRvIII	5	34.3×	2e-05
PI3K events in ERBB2 signaling	5	32.3×	3e-05
SHC1 events in ERBB2 signaling	7	32.0×	3e-07
Signaling by ERBB2 TMD/JMD mutants	7	32.0×	3e-07
Downregulation of ERBB2 signaling	8	29.3×	1e-07
Signaling by ERBB2 KD Mutants	7	28.5×	5e-07
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	27.4×	4e-05
Signaling by ERBB2	6	20.0×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine dephosphorylation	6	37.7×	4e-06
negative regulation of epidermal growth factor receptor signaling pathway	5	27.2×	2e-04
protein refolding	5	22.1×	4e-04
protein dephosphorylation	12	18.9×	2e-09
negative regulation of T cell receptor signaling pathway	5	13.0×	4e-03
epidermal growth factor receptor signaling pathway	7	12.3×	3e-04
cellular response to epidermal growth factor stimulus	5	11.3×	6e-03
T cell activation	6	11.0×	2e-03

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

ERBB2, commonly referred to as HER2, is amplified and/or overexpressed in 20-30% of invasive breast carcinomas. HER2-positive breast cancer is treated in a separate manner from other subtypes of breast cancer and commonly presents as more aggressive disease. Metastatic HER2-positive breast cancer is now commonly treated with HER2-targeted therapy. Apart from being amplified/overexpressed, ERBB2 activating mutations have been shown to have clinical importance in HER2-negative breast cancer. These mutations have shown sensitivity to the tyrosine kinase inhibitor neratinib, and highlight the importance of clinical sequencing efforts in treating breast cancer.

From intOGen — cancer-driver classification: activating (oncogene-like) across 16 cancer types — BLCA, BRCA, CESC, CHOL, COADREAD, EGC, ESCA, ESCC, LMS, LUAD, NSCLC, OVT…(+4 more).

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	9
Uncertain significance	386
Likely benign	326
Benign	36

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1188812	NM_004448.4(ERBB2):c.2129C>T (p.Ala710Val)	Pathogenic
13876	NM_004448.4(ERBB2):c.2328_2336dup (p.Val777_Ser779dup)	Pathogenic
13878	NM_004448.4(ERBB2):c.2740G>A (p.Glu914Lys)	Pathogenic
13879	NM_004448.4(ERBB2):c.2326G>A (p.Gly776Ser)	Pathogenic
13880	NM_004448.4(ERBB2):c.2570A>G (p.Asn857Ser)	Pathogenic
2582232	NM_004448.4(ERBB2):c.2089G>A (p.Val697Met)	Pathogenic
2582233	NM_004448.4(ERBB2):c.2515G>A (p.Val839Met)	Pathogenic
2582288	NM_004448.4(ERBB2):c.925G>A (p.Gly309Arg)	Pathogenic
2582289	NM_004448.4(ERBB2):c.1958C>T (p.Ser653Phe)	Pathogenic
376138	NM_004448.4(ERBB2):c.926G>A (p.Gly309Glu)	Pathogenic
376188	NM_004448.4(ERBB2):c.929C>A (p.Ser310Tyr)	Pathogenic
431024	NM_004448.4(ERBB2):c.2606T>G (p.Leu869Arg)	Pathogenic
44992	NM_004448.4(ERBB2):c.2331_2339dup (p.Gly778_Pro780dup)	Pathogenic
998138	NM_004448.4(ERBB2):c.3484_3485insG (p.Pro1162fs)	Pathogenic
998139	NM_004448.4(ERBB2):c.1610del (p.Gly537fs)	Pathogenic
13875	NM_004448.4(ERBB2):c.2313_2324dup (p.Tyr772_Ala775dup)	Likely pathogenic
163409	NM_004448.4(ERBB2):c.2325_2326insTCCGTGATGGCT (p.Ala775_Gly776insSerValMetAla)	Likely pathogenic
179590	NM_004448.4(ERBB2):c.2324_2325insCTCCGTGATGGC (p.Ala775_Gly776insSerValMetAla)	Likely pathogenic
44985	NM_004448.4(ERBB2):c.2314_2325dup (p.Tyr772_Ala775dup)	Likely pathogenic
44986	NM_004448.4(ERBB2):c.2320del (p.Met774fs)	Likely pathogenic
44988	NM_004448.4(ERBB2):c.2326_2327insTGT (p.Gly776delinsValCys)	Likely pathogenic
44989	NM_004448.4(ERBB2):c.2326_2327insTTT (p.Gly776delinsValCys)	Likely pathogenic
44990	NM_004448.4(ERBB2):c.2326delinsTTAT (p.Gly776delinsLeuCys)	Likely pathogenic
44993	NM_004448.4(ERBB2):c.2332_2340dup (p.Gly778_Pro780dup)	Likely pathogenic

SpliceAI

4562 predictions. Top by Δscore:

Variant	Effect	Δscore
17:39706986:CCA:C	acceptor_loss	1.0000
17:39706988:A:AG	acceptor_gain	1.0000
17:39706988:A:AT	acceptor_loss	1.0000
17:39706988:AGT:A	acceptor_gain	1.0000
17:39706988:AGTGT:A	acceptor_gain	1.0000
17:39706989:G:GG	acceptor_gain	1.0000
17:39706989:GT:G	acceptor_gain	1.0000
17:39706989:GTG:G	acceptor_gain	1.0000
17:39706989:GTGT:G	acceptor_gain	1.0000
17:39706989:GTGTG:G	acceptor_gain	1.0000
17:39707137:TGCAG:T	donor_loss	1.0000
17:39707138:GCAGG:G	donor_loss	1.0000
17:39707139:CAG:C	donor_loss	1.0000
17:39707140:AGG:A	donor_loss	1.0000
17:39707141:GGTGA:G	donor_loss	1.0000
17:39707142:G:T	donor_loss	1.0000
17:39707143:T:A	donor_loss	1.0000
17:39709316:A:AG	acceptor_gain	1.0000
17:39709317:G:GG	acceptor_gain	1.0000
17:39709317:GA:G	acceptor_gain	1.0000
17:39709449:GCCT:G	donor_gain	1.0000
17:39709452:TG:T	donor_loss	1.0000
17:39709453:G:C	donor_loss	1.0000
17:39709453:G:GG	donor_gain	1.0000
17:39709454:T:A	donor_loss	1.0000
17:39709877:GAGCC:G	donor_gain	1.0000
17:39709879:GCC:G	donor_gain	1.0000
17:39709893:G:GT	donor_gain	1.0000
17:39709894:G:T	donor_gain	1.0000
17:39710084:A:AG	acceptor_gain	1.0000

AlphaMissense

8156 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:39723596:T:C	L715P	1.000
17:39723599:A:T	K716I	1.000
17:39723611:T:C	L720P	1.000
17:39723631:G:A	G727R	1.000
17:39723631:G:C	G727R	1.000
17:39723632:G:A	G727E	1.000
17:39723637:G:C	G729R	1.000
17:39723637:G:T	G729C	1.000
17:39723638:G:A	G729D	1.000
17:39723643:T:A	F731I	1.000
17:39723643:T:C	F731L	1.000
17:39723644:T:C	F731S	1.000
17:39723644:T:G	F731C	1.000
17:39723645:T:A	F731L	1.000
17:39723645:T:G	F731L	1.000
17:39723646:G:C	G732R	1.000
17:39723646:G:T	G732C	1.000
17:39723647:G:A	G732D	1.000
17:39723647:G:T	G732V	1.000
17:39723653:T:A	V734D	1.000
17:39723912:G:C	G737R	1.000
17:39723913:G:A	G737D	1.000
17:39723918:T:A	W739R	1.000
17:39723918:T:C	W739R	1.000
17:39723954:G:C	A751P	1.000
17:39723955:C:A	A751D	1.000
17:39723960:A:G	K753E	1.000
17:39723961:A:T	K753I	1.000
17:39723962:A:C	K753N	1.000
17:39723962:A:T	K753N	1.000

dbSNP variants (sampled 300 via entrez): RS1000103734 (17:39712553 G>A,T), RS1000191737 (17:39702377 G>A), RS1000200425 (17:39694872 G>T), RS1000371669 (17:39725566 A>G), RS1000425427 (17:39726023 C>T), RS1000536949 (17:39707945 G>A), RS1000560046 (17:39703554 C>T), RS1000635791 (17:39700587 T>C), RS1000740767 (17:39709939 C>A,G,T), RS1000808875 (17:39708515 G>A,C), RS1000908318 (17:39707536 C>T), RS1000931450 (17:39690040 T>C), RS1000971422 (17:39721298 C>T), RS1001158511 (17:39694462 A>G,T), RS1001285665 (17:39689798 A>G)

Disease associations

OMIM: gene MIM:164870 | disease phenotypes: MIM:619465, MIM:114480, MIM:613659, MIM:167000, MIM:211980, MIM:137800, MIM:614286, MIM:114500, MIM:109800

GenCC curated gene-disease

Disease	Classification	Inheritance
Hirschsprung disease	Supportive	Autosomal dominant
lung cancer	Limited	Autosomal dominant
glioma susceptibility 1	Limited	Unknown
visceral neuropathy, familial, 2, autosomal recessive	Limited	Unknown

Mondo (15): visceral neuropathy, familial, 2, autosomal recessive (MONDO:0030399), hereditary breast carcinoma (MONDO:0016419), endometrial carcinoma (MONDO:0002447), ovarian neoplasm (MONDO:0021068), gastric cancer (MONDO:0001056), ovarian cancer (MONDO:0008170), lung cancer (MONDO:0008903), glioma susceptibility 1 (MONDO:0024498), myelodysplastic syndrome (MONDO:0018881), lung adenocarcinoma (MONDO:0005061), non-small cell lung carcinoma (MONDO:0005233), colorectal cancer (MONDO:0005575), prostate cancer (MONDO:0008315), urinary bladder cancer (MONDO:0001187), Hirschsprung disease (MONDO:0018309)

Orphanet (8): Hereditary breast cancer (Orphanet:227535), Rare ovarian cancer (Orphanet:213500), Myelodysplastic syndrome (Orphanet:52688), Familial prostate cancer (Orphanet:1331), NON RARE IN EUROPE: Adenocarcinoma of the lung (Orphanet:415268), NON RARE IN EUROPE: Non-small cell lung cancer (Orphanet:488201), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667), NON RARE IN EUROPE: Bladder cancer (Orphanet:157980)

HPO phenotypes

49 total (30 of 49 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000508	Ptosis
HP:0001442	Typified by somatic mosaicism
HP:0001510	Growth delay
HP:0001513	Obesity
HP:0001531	Failure to thrive in infancy
HP:0001561	Polyhydramnios
HP:0001762	Talipes equinovarus
HP:0001824	Weight loss
HP:0001864	Clinodactyly of the 5th toe
HP:0002014	Diarrhea
HP:0002017	Nausea and vomiting
HP:0002019	Constipation
HP:0002020	Gastroesophageal reflux
HP:0002027	Abdominal pain
HP:0002251	Aganglionic megacolon
HP:0002716	Lymphadenopathy
HP:0002888	Ependymoma
HP:0003002	Breast carcinoma
HP:0003270	Abdominal distention
HP:0003477	Peripheral axonal neuropathy
HP:0003593	Infantile onset
HP:0004322	Short stature
HP:0004387	Enterocolitis
HP:0005214	Intestinal obstruction
HP:0006519	Alveolar cell carcinoma
HP:0006774	Ovarian papillary adenocarcinoma
HP:0008872	Feeding difficulties in infancy

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST000624_15	Ulcerative colitis	3.000000e-08
GCST003144_8	Polycystic ovary syndrome	1.000000e-06
GCST003155_23	Systemic lupus erythematosus	8.000000e-09
GCST003724_6	Bipolar disorder	5.000000e-09
GCST005212_9	Asthma	2.000000e-30
GCST005752_156	Systemic lupus erythematosus	2.000000e-12
GCST007235_3	Pancreatic ductal adenocarcinoma	1.000000e-06
GCST007266_5	Adult asthma	4.000000e-12
GCST007564_21	Asthma or allergic disease (pleiotropy)	4.000000e-17
GCST008747_86	Estimated glomerular filtration rate	8.000000e-29
GCST008916_10	Asthma	5.000000e-09
GCST008916_21	Asthma	2.000000e-62
GCST008916_45	Asthma	3.000000e-10
GCST008916_86	Asthma	2.000000e-14
GCST010002_123	Refractive error	1.000000e-24
GCST012465_35	Bipolar disorder	3.000000e-08
GCST012465_43	Bipolar disorder	2.000000e-08

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D002289	Carcinoma, Non-Small-Cell Lung	C04.588.894.797.520.109.220.249; C08.381.540.140.500; C08.785.520.100.220.500
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
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
C562840	Breast Cancer, Familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (6): CHEMBL1824 (SINGLE PROTEIN), CHEMBL2111431 (PROTEIN FAMILY), CHEMBL2363049 (PROTEIN FAMILY), CHEMBL4106134 (PROTEIN COMPLEX), CHEMBL4630723 (PROTEIN COMPLEX), CHEMBL5465227 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

83 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 331,981 (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
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL1079742	ERLOTINIB HYDROCHLORIDE	4	13,852
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1173655	AFATINIB	4	15,144
CHEMBL1201179	LAPATINIB DITOSYLATE	4	3,017
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL180022	NERATINIB	4	9,404
CHEMBL1873475	IBRUTINIB	4	7,994
CHEMBL2105712	AFATINIB DIMALEATE	4	3,215
CHEMBL2105717	CABOZANTINIB	4	11,177
CHEMBL2105719	DACOMITINIB	4	750
CHEMBL2110732	DACOMITINIB ANHYDROUS	4	6,578
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL24944	TRIBROMSALAN	4	2,453
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL290106	BITHIONOL	4	6,439
CHEMBL296419	ASTEMIZOLE	4	21,577
CHEMBL305660	EBASTINE	4	10,024
CHEMBL3353410	OSIMERTINIB	4	8,898
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL3707348	ACALABRUTINIB	4
CHEMBL3936761	ZANUBRUTINIB	4
CHEMBL3989868	TUCATINIB	4
CHEMBL4071161	TIRABRUTINIB	4
CHEMBL428647	PACLITAXEL	4
CHEMBL4558324	LAZERTINIB	4
CHEMBL496	HEXACHLOROPHENE	4
CHEMBL53463	DOXORUBICIN	4
CHEMBL5416410	DASATINIB	4
CHEMBL553	ERLOTINIB	4

Clinical evidence (CIViC)

Drug × variant × indication: 183 predictive associations from 208 curated evidence items; also 12 oncogenic, 10 functional, 3 prognostic.

Variant	Therapy	Indication	Effect	Level	CIViC
ERBB2 Amplification	Trastuzumab + Neratinib	Her2-receptor Positive Breast Cancer	Sensitivity/Response	CIViC A	EID1113 +2
ERBB2 Amplification	Trastuzumab	Her2-receptor Positive Breast Cancer	Sensitivity/Response	CIViC A	EID1122 +2
ERBB2 Amplification	Trastuzumab	Gastric Adenocarcinoma	Sensitivity/Response	CIViC A	EID1499 +1
ERBB2 Amplification	Capecitabine + Neratinib	Her2-receptor Positive Breast Cancer	Sensitivity/Response	CIViC A	EID8048 +1
ERBB2 Exon 20 Insertion	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11765 +1
ERBB2 A775_G776insTVMA	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11755
ERBB2 A775_G776insV	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11756
ERBB2 A775_G776insVVMA	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11757
ERBB2 A775_G776insYVMA	Zongertinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID12564
ERBB2 Amplification	Capecitabine + Lapatinib	Breast Cancer	Sensitivity/Response	CIViC A	EID11247
ERBB2 Amplification	Lapatinib + Letrozole	Breast Cancer	Sensitivity/Response	CIViC A	EID11248
ERBB2 Amplification	Margetuximab	Breast Cancer	Sensitivity/Response	CIViC A	EID11249
ERBB2 Amplification	Trastuzumab + Tucatinib + Capecitabine	Breast Cancer	Sensitivity/Response	CIViC A	EID11250
ERBB2 Amplification	Pembrolizumab + Trastuzumab + Chemotherapy	Stomach Cancer	Sensitivity/Response	CIViC A	EID11251
ERBB2 Amplification	Pembrolizumab + Trastuzumab + Chemotherapy	Gastroesophageal Junction Adenocarcinoma	Sensitivity/Response	CIViC A	EID11252
ERBB2 Amplification	Trastuzumab	Stomach Cancer	Sensitivity/Response	CIViC A	EID11253
ERBB2 Amplification	Trastuzumab	Gastroesophageal Junction Adenocarcinoma	Sensitivity/Response	CIViC A	EID11254
ERBB2 Amplification	Trastuzumab + Chemotherapy	Gastroesophageal Junction Adenocarcinoma	Sensitivity/Response	CIViC A	EID11256
ERBB2 G776_V777delinsVCD	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11758
ERBB2 G776delinsLC	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11760
ERBB2 G776delinsVC	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11761
ERBB2 G778_P780dup	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11762
ERBB2 G778_S779insLPS	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11763
ERBB2 Kinase Domain Mutation OR ERBB2 Exon 20 Insertion	Sevabertinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID12808
ERBB2 L755A	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11752
ERBB2 L755M	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11753
ERBB2 L755P	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11754
ERBB2 L755P OR ERBB2 G776V OR ERBB2 G776delinsVC OR ERBB2 P780_Y781insGSP	Zongertinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID12563
ERBB2 L755S	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID12233
ERBB2 L755W	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID12234

+153 more predictive associations (showing top 30 by evidence level).

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1136201	Toxicity	3	trastuzumab	Breast Neoplasms;Drug Toxicity
rs1136201	Efficacy	3	carboplatin;docetaxel;trastuzumab	Breast Neoplasms

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1136201	ERBB2	3	2.50	2	trastuzumab;carboplatin;docetaxel;trastuzumab
rs1058808	ERBB2		0.00	0

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 (32 total), top 25:

Ligand	Action	Affinity	Parameter
MM-111	Binding	9.52	pKd
EGFR/ErbB-2/ErbB-4 inhibitor	Inhibition	8.96	pIC50
allitinib	Inhibition	8.52	pIC50
tuxobertinib	Inhibition	8.3	pIC50
poziotinib	Inhibition	8.28	pIC50
mubritinib	Inhibition	8.22	pIC50
AEE788	Inhibition	8.22	pIC50
pirotinib	Inhibition	8.19	pIC50
ibrutinib	Inhibition	8.19	pIC50
tucatinib	Inhibition	8.16	pIC50
compound 38 [PMID: 24915291]	Inhibition	8.15	pIC50
selatinib	Inhibition	8.07	pIC50
canertinib	Inhibition	8.05	pIC50
bizrolertinib	Inhibition	8.02	pIC50
pertuzumab	Inhibition	8.0	pIC50
mifanertinib	Inhibition	7.93	pIC50
CP-724714	Inhibition	7.92	pIC50
zongertinib	Inhibition	7.89	pIC50
lapatinib	Inhibition	7.89	pKi
afatinib	Inhibition	7.85	pIC50
sapitinib	Inhibition	7.85	pIC50
tesevatinib	Inhibition	7.8	pIC50
CUDC-101	Inhibition	7.8	pIC50
BMS-690514	Inhibition	7.72	pIC50
BMS-599626	Inhibition	7.49	pIC50

Binding affinities (BindingDB)

965 measured of 999 human assays (1407 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-[4-[[(12aS)-8-methoxy-6-oxo-12a,13-dihydroindolo[2,1-c][1,4]benzodiazepin-9-yl]oxy]butanoylamino]-N-[5-[[5-(5-aminoindole-1-carbonyl)-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1-methylimidazole-2-carboxamide	IC50	0.06 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-[[5-(5-aminoindazole-1-carbonyl)-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1-methylimidazole-2-carboxamide	IC50	0.09 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
(E)-N-[4-(3-chloro-4-fluoroanilino)-7-(3-oxabicyclo[3.1.0]hexan-6-ylmethoxy)quinazolin-6-yl]-4-(dimethylamino)but-2-enamide	IC50	0.13 nM	US-9187459: Quinazoline-7-ether compounds and methods of use
methyl 1-[4-[[4-[[4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-1-methylimidazole-2-carbonyl]amino]-1-methylpyrrole-2-carbonyl]amino]-1-methylpyrrole-2-carbonyl]indole-5-carboxylate	IC50	0.14 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-[[5-(5-aminoindole-1-carbonyl)-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1-methylimidazole-2-carboxamide	IC50	0.15 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-[[5-(5-methoxyindole-1-carbonyl)-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1-methylimidazole-2-carboxamide	IC50	0.15 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-[[5-(6-aminoindazole-1-carbonyl)-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1-methylimidazole-2-carboxamide	IC50	0.16 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-[[5-[5-(aminomethyl)indole-1-carbonyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1-methylimidazole-2-carboxamide	IC50	0.18 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-1-methyl-N-[1-methyl-5-[[1-methyl-5-(5-methylsulfanylindole-1-carbonyl)pyrrol-3-yl]carbamoyl]pyrrol-3-yl]imidazole-2-carboxamide	IC50	0.2 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
(2E)-N-{4-[(3-bromophenyl)amino]quinazolin-6-yl}-4-(dimethylamino)but-2-enamide	IC50	0.22 nM
4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-[[5-(6-aminoindole-1-carbonyl)-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1-methylimidazole-2-carboxamide	IC50	0.28 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
2-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-[[5-(5-aminoindole-1-carbonyl)-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1,3-thiazole-4-carboxamide	IC50	0.3 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
(E)-N-[4-(3-chloro-4-fluoroanilino)-7-(3-oxabicyclo[3.1.0]hexan-1-ylmethoxy)quinazolin-6-yl]-4-(dimethylamino)but-2-enamide	IC50	0.37 nM	US-9187459: Quinazoline-7-ether compounds and methods of use
N-[4-(3-chloro-4- fluorophenylamino)-7-(2-(6-methyl- 6-azaspiro[2.5]octan-1- yl)ethoxy)quinazolin-6-yl]- acrylamide	IC50	0.39 nM	US-9730934: Quinazoline derivatives substituted by aniline, preparation method and use thereof
(E)-N-[4-(3-chloro-4-fluoroanilino)-7-[[(3R,6R)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]quinazolin-6-yl]-4-(dimethylamino)but-2-enamide	IC50	0.4 nM	US-9187459: Quinazoline-7-ether compounds and methods of use
4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-(5-aminoindole-1-carbonyl)-1-methylpyrrol-3-yl]-1-methylimidazole-2-carboxamide	IC50	0.4 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
(E)-N-[4-(3-chloro-4-fluoroanilino)-7-[[(1R,5R)-3-oxabicyclo[3.1.0]hexan-1-yl]methoxy]quinazolin-6-yl]-4-(dimethylamino)but-2-enamide	IC50	0.51 nM	US-9187459: Quinazoline-7-ether compounds and methods of use
(E)-N-[4-(3-chloro-4-fluoroanilino)-7-[[(1S,5S)-3-oxabicyclo[3.1.0]hexan-1-yl]methoxy]quinazolin-6-yl]-5-(dimethylamino)pent-2-enamide	IC50	0.54 nM	US-9187459: Quinazoline-7-ether compounds and methods of use
(2E)-N-{4-[(3-bromophenyl)amino]quinazolin-6-yl}but-2-enamide	IC50	0.55 nM
N-[4-(3-chloro-4- fluorophenylamino)-7-(2-(7-methyl- 7-azaspiro[3.5]nonan-2- yl)ethoxy)quinazolin-6-yl]- acrylamide	IC50	0.56 nM	US-9730934: Quinazoline derivatives substituted by aniline, preparation method and use thereof
methyl 1-[4-[[4-[[4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-1-methylimidazole-2-carbonyl]amino]-1-methylpyrrole-2-carbonyl]amino]-1-methylpyrrole-2-carbonyl]pyrrolo[2,3-b]pyridine-5-carboxylate	IC50	0.58 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
1-[4-[4-[3-chloro-2-fluoro-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)anilino]-7-methoxypyrido[3,2-d]pyrimidin-6-yl]piperazin-1-yl]prop-2-en-1-one	IC50	0.6 nM	US-12447153: HER2 mutation inhibitors
4-[4-[[(6aS)-2-hydroxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-1-methyl-N-[1-methyl-5-(1H-pyrrolo[2,3-b]pyridin-5-ylcarbamoyl)pyrrol-3-yl]imidazole-2-carboxamide	IC50	0.66 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
N-[4-(3-chloro-4- fluorophenylamino)-7-(2- ((1R,5S,6S)-3-methyl-3- azabicyclo[3.1.0]hexan-6- ylethoxy)quinazolin-6-yl]- acrylamide	IC50	0.66 nM	US-9730934: Quinazoline derivatives substituted by aniline, preparation method and use thereof
4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-[[5-(4-aminoindole-1-carbonyl)-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1-methylimidazole-2-carboxamide	IC50	0.67 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
(E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-ethoxyethoxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide	IC50	0.699 nM	US-10196365: Quinazoline derivative, preparation method therefor, and pharmaceutical composition and application thereof
(E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(3-methoxypropoxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide	IC50	0.765 nM	US-10196365: Quinazoline derivative, preparation method therefor, and pharmaceutical composition and application thereof
(E)-N-(7-(2-ethoxyethoxy)-4-(3-ethynylphenylamino)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide	IC50	0.771 nM	US-10196365: Quinazoline derivative, preparation method therefor, and pharmaceutical composition and application thereof
N-[4-(3-chloro-4- fluorophenylamino)-7-(2-(3-methyl- 3-azabicyclo[3.2.1]octan-8- yl)ethoxy)quinazolin-6-yl]- acrylamide	IC50	0.8 nM	US-9730934: Quinazoline derivatives substituted by aniline, preparation method and use thereof
IBRUTINIB	IC50	0.8 nM	US-9278100: Inhibitors of bruton’s tyrosine kinase for the treatment of solid tumors
N-[4-(3-chloro-4- fluorophenylamino)-7-(8-methyl-1- oxa-8-azaspiro[4.5]decan-2- ylmethoxy)quinazolin-6-yl]- acrylamide	IC50	0.93 nM	US-9730934: Quinazoline derivatives substituted by aniline, preparation method and use thereof
(R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-methoxy-1-methylethoxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide	IC50	0.95 nM	US-10196365: Quinazoline derivative, preparation method therefor, and pharmaceutical composition and application thereof
4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-(5-amino-1,3-dihydroisoindole-2-carbonyl)-1-methylpyrrol-3-yl]-1-methylimidazole-2-carboxamide	IC50	0.97 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
N-[4-(3-chloro-4- fluorophenylamino)-7-((8-methyl-1- oxa-8-azaspiro[4.5]decan-3- yl)methoxy)quinazolin-6-yl]- acrylamide	IC50	1 nM	US-9730934: Quinazoline derivatives substituted by aniline, preparation method and use thereof
N-[4-(3-chloro-4- fluorophenylamino)-7-((7-methyl-7- azaspiro[3.5]nonan-2- yl)methoxy)quinazolin-6-yl]- acrylamide	IC50	1 nM	US-9730934: Quinazoline derivatives substituted by aniline, preparation method and use thereof
N-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl]prop-2-enamide	IC50	1.1 nM	US-9278100: Inhibitors of bruton’s tyrosine kinase for the treatment of solid tumors
3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	IC50	1.18 nM	US-8822500: Tyrosine kinase inhibitors
6-Substituted 4-Anilinoquinazoline 9	IC50	1.2 nM
US12447153, Example 299	IC50	1.2 nM	US-12447153: HER2 mutation inhibitors
(R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-methoxyethoxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide	IC50	1.4 nM	US-9714235: Quinazoline derivatives, compositions thereof, and use as pharmaceuticals
4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-[[5-(5-amino-2,3-dihydroindole-1-carbonyl)-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1-methylimidazole-2-carboxamide	IC50	1.4 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
(E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-ethoxyethoxy)quinazolin-6-yl)-4-(diethylamino)but-2-enamide	IC50	1.49 nM	US-10196365: Quinazoline derivative, preparation method therefor, and pharmaceutical composition and application thereof
4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-[[5-(5-amino-1,3-dihydroisoindole-2-carbonyl)-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1-methylimidazole-2-carboxamide	IC50	1.5 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
4-[4-[[(12aS)-8-methoxy-6-oxo-12a,13-dihydroindolo[2,1-c][1,4]benzodiazepin-9-yl]oxy]butanoylamino]-N-[5-[[5-(3-hydroxypropylcarbamoyl)-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1-methylpyrrole-2-carboxamide	IC50	1.5 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
(E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-isopropoxyethoxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide	IC50	1.54 nM	US-10196365: Quinazoline derivative, preparation method therefor, and pharmaceutical composition and application thereof
(R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide	IC50	1.6 nM	US-9714235: Quinazoline derivatives, compositions thereof, and use as pharmaceuticals
1-[7-[4-[3-chloro-2-fluoro-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octan-4-yl]prop-2-en-1-one	IC50	1.8 nM	US-12447153: HER2 mutation inhibitors
1-[4-[4-[3-chloro-2-fluoro-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]azepan-1-yl]prop-2-en-1-one	IC50	1.9 nM	US-12447153: HER2 mutation inhibitors
(R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-ethoxyquinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide	IC50	2 nM	US-9714235: Quinazoline derivatives, compositions thereof, and use as pharmaceuticals
4-[4-[[(6aR)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-[[5-(3-hydroxypropylcarbamoyl)-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1-methylpyrrole-2-carboxamide	IC50	2 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof

ChEMBL bioactivities

3453 potent at pChembl≥5 of 3763 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.40	IC50	0.04	nM	CHEMBL6132997
10.22	IC50	0.06	nM	IMATINIB
10.22	IC50	0.06	nM	CHEMBL5939267
10.05	IC50	0.09	nM	CHEMBL6019933
9.85	IC50	0.14	nM	CHEMBL5221067
9.85	IC50	0.14	nM	CHEMBL5966664
9.82	IC50	0.15	nM	CHEMBL5902815
9.82	IC50	0.15	nM	CHEMBL5980010
9.80	IC50	0.16	nM	CHEMBL5178703
9.80	IC50	0.16	nM	CHEMBL6019427
9.74	IC50	0.18	nM	CHEMBL6036674
9.70	IC50	0.2	nM	CHEMBL5956952
9.55	IC50	0.28	nM	CHEMBL5929658
9.54	IC50	0.29	nM	CHEMBL5939267
9.52	IC50	0.3	nM	CHEMBL5980010
9.52	IC50	0.3	nM	CHEMBL5955178
9.51	IC50	0.31	nM	CHEMBL6019933
9.47	IC50	0.34	nM	CHEMBL5977738
9.46	IC50	0.35	nM	CHEMBL5956952
9.40	IC50	0.4	nM	CHEMBL5853980
9.38	IC50	0.42	nM	CHEMBL5178703
9.37	IC50	0.43	nM	CHEMBL5178703
9.37	IC50	0.43	nM	CHEMBL5902815
9.30	IC50	0.5	nM	CHEMBL3344216
9.30	IC50	0.5	nM	CHEMBL437890
9.30	IC50	0.5	nM	CHEMBL204638
9.26	IC50	0.55	nM	CHEMBL5966664
9.25	IC50	0.56	nM	CHEMBL5178703
9.25	IC50	0.56	nM	SORAFENIB
9.24	IC50	0.58	nM	CHEMBL5978603
9.23	IC50	0.59	nM	CHEMBL5956952
9.22	IC50	0.6	nM	CHEMBL5980010
9.22	IC50	0.6	nM	CHEMBL6019427
9.22	IC50	0.6	nM	CHEMBL5881155
9.20	IC50	0.63	nM	CHEMBL5939267
9.18	IC50	0.66	nM	CHEMBL6019933
9.18	IC50	0.66	nM	CHEMBL5850421
9.17	IC50	0.67	nM	CHEMBL5876925
9.16	IC50	0.69	nM	CHEMBL2387001
9.15	IC50	0.7	nM	CHEMBL203599
9.15	IC50	0.7	nM	CHEMBL204638
9.15	IC50	0.7	nM	CHEMBL5955178
9.14	IC50	0.73	nM	CHEMBL5929658
9.12	Kd	0.75	nM	IBRUTINIB
9.10	IC50	0.8	nM	CHEMBL203661
9.10	IC50	0.8	nM	CHEMBL203599
9.09	IC50	0.81	nM	CHEMBL6036674
9.08	IC50	0.84	nM	CHEMBL5902815
9.08	IC50	0.83	nM	CHEMBL5966664
9.05	IC50	0.89	nM	CHEMBL2387000

PubChem BioAssay actives

2509 with measured affinity, of 5513 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
N-(3-cyano-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)-2-(1H-pyrazolo[5,4-b]pyridin-3-ylamino)acetamide	1916785: Inhibition of HER2 (unknown origin) incubated for 1 hr in presence of ATP by Kinase-Glo Plus luminescence kinase assay	ic50	0.0001	uM
Imatinib	1916785: Inhibition of HER2 (unknown origin) incubated for 1 hr in presence of ATP by Kinase-Glo Plus luminescence kinase assay	ic50	0.0001	uM
(Z)-N-[7-ethoxy-4-[3-methyl-4-([1,2,4]triazolo[4,3-c]pyrimidin-7-yloxy)anilino]quinazolin-6-yl]-2-fluoro-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide	1905774: Inhibition of HER2 V777L mutant (unknown origin) incubated for 120 mins in presence of 33P-ATP by P81 ion exchange cellulose chromatography	ic50	0.0002	uM
N-[4-(3-bromo-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-5-(4-methylpiperazin-1-yl)pent-2-ynamide	260896: Inhibition of erbB2 fusion protein expressed in baculovirus by ELISA	ic50	0.0005	uM
N-[4-(3-bromo-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-5-morpholin-4-ylpent-2-ynamide	260899: Inhibition of HER stimulated human erbB autophosphorylation in MDA-MB-453 cells	ic50	0.0005	uM
N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(1S)-1-(dimethylamino)-2-methylsulfonylethyl]furan-2-yl]quinazolin-4-amine	1168534: Inhibition of HER2 (unknown origin) assessed as reduction in autophosphorylation by ELISA method	ic50	0.0005	uM
N-[4-(3-chloro-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-5-(4-methylpiperazin-1-yl)pent-2-ynamide	260896: Inhibition of erbB2 fusion protein expressed in baculovirus by ELISA	ic50	0.0007	uM
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
N-[4-(3-chloro-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-5-morpholin-4-ylpent-2-ynamide	260896: Inhibition of erbB2 fusion protein expressed in baculovirus by ELISA	ic50	0.0008	uM
Ibrutinib	1878102: Binding affinity to ERBB2 (unknown origin) assessed as dissociation constant by KINOMEscan analysis	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
(2S)-N-[2-[4-[4-(1,2-benzothiazol-4-yloxy)-3-chloroanilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]pyrrolidine-2-carboxamide;hydrochloride	670126: Inhibition of N-terminus peptide-tagged human recombinant HER2 expressed using baculovirus infection system using [gamma-33P]-ATP preincubated with compound for 5 mins measured after 10 mins by scintillation counting	ic50	0.0009	uM
(2R)-2-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]quinazolin-5-yl]oxy-N,N-dimethylpropanamide	315250: Inhibition of ebrB2	ic50	0.0010	uM
1-[4-[2-[[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-1H-pyrazolo[5,4-d]pyrimidin-3-yl]oxy]ethyl]piperazin-1-yl]ethanone	320572: Inhibition of erbB2	ic50	0.0010	uM
N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-3-(2-morpholin-4-ylethoxy)-1H-pyrazolo[5,4-d]pyrimidin-4-amine	320572: Inhibition of erbB2	ic50	0.0010	uM
1-[2-[[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-1H-pyrazolo[5,4-d]pyrimidin-3-yl]oxy]ethyl]piperidin-4-ol	320572: Inhibition of erbB2	ic50	0.0010	uM
1-[2-[[4-[4-[(3-fluorophenyl)methoxy]-3-methylanilino]-1H-pyrazolo[5,4-d]pyrimidin-3-yl]oxy]ethyl]piperidin-4-ol	320572: Inhibition of erbB2	ic50	0.0010	uM
N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-3-[2-(4-methylpiperazin-1-yl)ethoxy]-1H-pyrazolo[5,4-d]pyrimidin-4-amine	320572: Inhibition of erbB2	ic50	0.0010	uM
N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-3-(3-morpholin-4-ylpropoxy)-1H-pyrazolo[5,4-d]pyrimidin-4-amine	320572: Inhibition of erbB2	ic50	0.0010	uM
1-[2-[[4-[3-chloro-4-[(6-methyl-3-pyridinyl)oxy]anilino]-1H-pyrazolo[5,4-d]pyrimidin-3-yl]oxy]ethyl]piperidin-4-ol	320572: Inhibition of erbB2	ic50	0.0010	uM
(2R)-N,N-dimethyl-2-[4-[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]anilino]quinazolin-5-yl]oxypropanamide	315250: Inhibition of ebrB2	ic50	0.0010	uM
N-[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]-5-[(2R)-1-(dimethylamino)propan-2-yl]oxyquinazolin-4-amine	404519: Inhibition of HER2	ic50	0.0010	uM
4-chloro-2-[5-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-isoquinolin-6-yl-2-pyridinyl]phenol	1450721: Inhibition of recombinant ErbB2 (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 60 mins by ELISA	ic50	0.0010	uM
5-fluoro-2-[5-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-(3-methyl-2H-indazol-5-yl)-2-pyridinyl]phenol	1450721: Inhibition of recombinant ErbB2 (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 60 mins by ELISA	ic50	0.0010	uM
4-chloro-2-[5-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-(3-methyl-2H-indazol-5-yl)-2-pyridinyl]phenol	1450721: Inhibition of recombinant ErbB2 (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 60 mins by ELISA	ic50	0.0010	uM
1-[4-[4-(3,4-dichloro-2-fluoroanilino)-7-[(3S)-oxolan-3-yl]oxyquinazolin-6-yl]oxypiperidin-1-yl]prop-2-en-1-one	1951290: Inhibition of HER2 (unknown origin)	ic50	0.0010	uM
N-(1-benzylindazol-5-yl)-6-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]quinazolin-4-amine	404519: Inhibition of HER2	ic50	0.0010	uM
2-amino-N-[2-[4-[4-(1,2-benzothiazol-4-yloxy)-3-chloroanilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]-2-methylpropanamide	670126: Inhibition of N-terminus peptide-tagged human recombinant HER2 expressed using baculovirus infection system using [gamma-33P]-ATP preincubated with compound for 5 mins measured after 10 mins by scintillation counting	ic50	0.0010	uM
N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-3-[2-(oxazepan-2-yl)ethoxy]-1H-pyrazolo[5,4-d]pyrimidin-4-amine	320572: Inhibition of erbB2	ic50	0.0010	uM
N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[1-(methylamino)-2-methylsulfonylethyl]furan-2-yl]quinazolin-4-amine	1168534: Inhibition of HER2 (unknown origin) assessed as reduction in autophosphorylation by ELISA method	ic50	0.0010	uM
Neratinib	410944: Inhibition of ERBb2 by HTRF assay	ic50	0.0010	uM
N-[4-(3-bromo-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]prop-2-enamide	68096: Inhibition of heregulin-stimulated autophosphorylation of ERBB2 receptor kinase in MDA-MB-453 cells.	ic50	0.0011	uM
N-[4-(3-chloro-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]but-2-ynamide	260896: Inhibition of erbB2 fusion protein expressed in baculovirus by ELISA	ic50	0.0011	uM
(E)-N-[7-hydroxy-4-(4-imidazo[1,2-c]pyrimidin-7-yloxy-3-methylanilino)quinazolin-6-yl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide	1905726: Inhibition of wild type human GST-tagged HER2 (676 to end residues) expressed in baculovirus infected Sf9 cells incubated for 30 mins in presence of ATP by HTRF analysis	ic50	0.0011	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
1-[4-[4-(3,4-dichloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]prop-2-en-1-one	1951290: Inhibition of HER2 (unknown origin)	ic50	0.0013	uM
6-[2-chloro-4-[[5-(2-hydroxyethyl)pyrrolo[3,2-d]pyrimidin-4-yl]amino]phenoxy]-2,3-dihydroisoindol-1-one	670126: Inhibition of N-terminus peptide-tagged human recombinant HER2 expressed using baculovirus infection system using [gamma-33P]-ATP preincubated with compound for 5 mins measured after 10 mins by scintillation counting	ic50	0.0013	uM
(E)-3-[(2R)-1-methylpyrrolidin-2-yl]-N-[4-[3-methyl-4-([1,2,4]triazolo[4,3-c]pyrimidin-7-yloxy)anilino]quinazolin-6-yl]prop-2-enamide	1905726: Inhibition of wild type human GST-tagged HER2 (676 to end residues) expressed in baculovirus infected Sf9 cells incubated for 30 mins in presence of ATP by HTRF analysis	ic50	0.0014	uM
(E)-N-[7-hydroxy-4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)anilino]quinazolin-6-yl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide	1905726: Inhibition of wild type human GST-tagged HER2 (676 to end residues) expressed in baculovirus infected Sf9 cells incubated for 30 mins in presence of ATP by HTRF analysis	ic50	0.0014	uM
1-[4-[4-(3-chloro-2-fluoroanilino)-7-[(3S)-oxolan-3-yl]oxyquinazolin-6-yl]oxypiperidin-1-yl]prop-2-en-1-one	1951290: Inhibition of HER2 (unknown origin)	ic50	0.0014	uM
(Z)-N-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-7-ethoxyquinazolin-6-yl]-4-(dimethylamino)-2-fluorobut-2-enamide	1171421: Inhibition of wild type HER2 (unknown origin) incubated for 5 mins by HTRF assay	ic50	0.0014	uM
(E)-N-[6-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-2,4,6-triazatricyclo[7.3.1.05,13]trideca-1(13),2,4,9,11-pentaen-10-yl]-4-(dimethylamino)but-2-enamide	2103212: Inhibition of wild type HER2 (unknown origin) using 4 x ULightTM-labeled Ploy GT peptide substrate measured after 180 mins	ic50	0.0015	uM
(E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-5-(3-methoxyphenyl)quinazolin-6-yl]-4-(dimethylamino)but-2-enamide	2103212: Inhibition of wild type HER2 (unknown origin) using 4 x ULightTM-labeled Ploy GT peptide substrate measured after 180 mins	ic50	0.0015	uM
7-[2-chloro-4-[[5-(2-hydroxyethyl)pyrrolo[3,2-d]pyrimidin-4-yl]amino]phenoxy]-1,3-dihydroindol-2-one	670126: Inhibition of N-terminus peptide-tagged human recombinant HER2 expressed using baculovirus infection system using [gamma-33P]-ATP preincubated with compound for 5 mins measured after 10 mins by scintillation counting	ic50	0.0015	uM
(E)-N-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-5-(3-methylphenyl)quinazolin-6-yl]-4-(dimethylamino)but-2-enamide	2103212: Inhibition of wild type HER2 (unknown origin) using 4 x ULightTM-labeled Ploy GT peptide substrate measured after 180 mins	ic50	0.0016	uM
4-[2-chloro-4-[[5-(2-hydroxyethyl)pyrrolo[3,2-d]pyrimidin-4-yl]amino]phenoxy]-1,3-dihydroindol-2-one	670126: Inhibition of N-terminus peptide-tagged human recombinant HER2 expressed using baculovirus infection system using [gamma-33P]-ATP preincubated with compound for 5 mins measured after 10 mins by scintillation counting	ic50	0.0016	uM
N-[2-[4-[4-(1,2-benzothiazol-4-yloxy)-3-chloroanilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]acetamide	670126: Inhibition of N-terminus peptide-tagged human recombinant HER2 expressed using baculovirus infection system using [gamma-33P]-ATP preincubated with compound for 5 mins measured after 10 mins by scintillation counting	ic50	0.0016	uM
(E)-N-[7-ethoxy-4-[3-methyl-4-([1,2,4]triazolo[4,3-c]pyrimidin-7-yloxy)anilino]quinazolin-6-yl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide	1905726: Inhibition of wild type human GST-tagged HER2 (676 to end residues) expressed in baculovirus infected Sf9 cells incubated for 30 mins in presence of ATP by HTRF analysis	ic50	0.0017	uM
(E)-N-[7-hydroxy-4-(4-imidazo[1,2-a]pyridin-7-yloxy-3-methylanilino)quinazolin-6-yl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide	1905726: Inhibition of wild type human GST-tagged HER2 (676 to end residues) expressed in baculovirus infected Sf9 cells incubated for 30 mins in presence of ATP by HTRF analysis	ic50	0.0017	uM
2-[4-[3-chloro-4-(1H-indazol-4-yloxy)anilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethanol	670126: Inhibition of N-terminus peptide-tagged human recombinant HER2 expressed using baculovirus infection system using [gamma-33P]-ATP preincubated with compound for 5 mins measured after 10 mins by scintillation counting	ic50	0.0017	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Fluorouracil	affects cotreatment, decreases activity, increases reaction, affects response to substance, increases expression (+5 more)	12
Doxorubicin	decreases reaction, decreases response to substance, affects expression, increases expression, affects cotreatment (+5 more)	11
sodium arsenite	increases activity, affects phosphorylation, increases reaction, increases phosphorylation, decreases expression (+7 more)	8
Lapatinib	decreases phosphorylation, increases reaction, affects reaction, decreases activity, decreases expression (+2 more)	8
Estradiol	affects cotreatment, decreases expression, increases expression, increases reaction, decreases reaction	7
Tamoxifen	decreases response to substance, increases activity, increases phosphorylation, decreases reaction, increases response to substance	7
Cisplatin	decreases reaction, decreases response to substance, affects cotreatment, decreases expression, increases expression (+1 more)	6
Curcumin	decreases response to substance, increases degradation, decreases expression, decreases phosphorylation, decreases reaction (+3 more)	6
Cyclophosphamide	affects cotreatment, affects response to substance, decreases response to substance	6
geldanamycin	increases degradation, affects binding, decreases reaction, increases reaction, decreases expression (+1 more)	5
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases expression, decreases reaction, increases degradation	5
Resveratrol	increases expression, increases reaction, affects cotreatment, decreases expression, decreases phosphorylation (+1 more)	5
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression, increases expression	5
Quercetin	decreases expression, affects cotreatment, affects binding, increases reaction, increases phosphorylation (+5 more)	5
Tetrachlorodibenzodioxin	affects expression, decreases expression, increases expression	5
bisphenol F	affects cotreatment, decreases methylation, increases expression	4
beta-hexachlorocyclohexane	affects binding, increases reaction, decreases reaction, increases activity, increases expression	4
Fulvestrant	increases expression, affects cotreatment, decreases methylation, affects response to substance, decreases expression (+1 more)	4
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression, decreases methylation (+1 more)	4
Cycloheximide	increases degradation, increases reaction, affects cotreatment, decreases expression	4
Etoposide	decreases expression, decreases reaction, decreases response to substance, affects response to substance, increases expression	4
Valproic Acid	affects expression, decreases expression	4
Paclitaxel	decreases reaction, decreases response to substance, decreases activity, decreases phosphorylation, increases reaction (+2 more)	4
arsenite	decreases expression, increases expression, increases phosphorylation, affects reaction, increases secretion (+3 more)	3
afimoxifene	affects binding, decreases reaction, increases reaction, decreases expression, decreases response to substance	3
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	affects binding, increases reaction, decreases expression, decreases reaction, decreases response to substance (+1 more)	3
tanespimycin	decreases expression, increases degradation	3
Docetaxel	affects cotreatment, affects response to substance, increases response to substance	3
Vorinostat	decreases expression, increases degradation, increases ubiquitination	3
Arsenic	affects phosphorylation, affects reaction, increases expression, affects expression, decreases expression (+5 more)	3

ChEMBL screening assays

1221 unique, capped per target: 1136 binding, 79 functional, 6 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1001230	Binding	Inhibition of ERBB2	The identification of pyrazolo[1,5-a]pyridines as potent p38 kinase inhibitors. — Bioorg Med Chem Lett
CHEMBL1963780	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: ERBB2	PubChem BioAssay data set
CHEMBL4023690	ADMET	Inhibition of recombinant human cytoplasmic His-tagged ERBB2 expressed in baculovirus at 1 uM by Z’-LYTE assay	Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton’s Tyrosine Kinase Inhibitor in Early Clinical Development. — J Med Chem

Cellosaurus cell lines

93 cell lines: 47 cancer cell line, 27 spontaneously immortalized cell line, 12 transformed cell line, 5 factor-dependent cell line, 2 conditionally immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0124	435.eB	Cancer cell line	Male
CVCL_0U80	MCF-7/HER2-18	Cancer cell line	Female
CVCL_1188	ECC10	Cancer cell line	Male
CVCL_1326	Karpas-45	Cancer cell line	Male
CVCL_1452	NCI-ADR-RES	Cancer cell line	Female
CVCL_1629	OVCAR-8	Cancer cell line	Female
CVCL_1661	ZR-75-30	Cancer cell line	Female
CVCL_1859	CCRF-HSB-2	Cancer cell line	Male
CVCL_1Y12	HSB2/GS	Cancer cell line	Male
CVCL_3033	MTSV1-7 ce1	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00158041	PHASE4	COMPLETED	Subcutaneous Amifostine Safety Study
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00365508	PHASE4	COMPLETED	Counseling and Nicotine Replacement Therapy in Helping Adult Smokers Quit Smoking
NCT00440960	PHASE4	COMPLETED	Anesthesia in Flexible Bronchoscopy for Lung Cancer Diagnostic
NCT00492843	PHASE4	TERMINATED	Loading Dose or Standard Dose of Intravenous Ibandronate in Treating Patients With Lung Cancer and Skeletal Metastasis
NCT00666978	PHASE4	COMPLETED	Health Education Counseling With or Without Bupropion in Helping African Americans Stop Smoking
NCT00675168	PHASE4	UNKNOWN	Positron Emission Tomography (PET)/Computed Tomography (CT) and Roentgen in Lung Cancer: Evaluation of Patients in General Practice
NCT00712647	PHASE4	COMPLETED	Carotene and Retinol Efficacy Trial
NCT00747773	PHASE4	COMPLETED	Cryospray Ablation of Surgical Resection Specimens To Determine Safety And Histological Effect In The Lung
NCT01060137	PHASE4	COMPLETED	Fentanyl Matrix in Lung Cancer Pain
NCT01381627	PHASE4	UNKNOWN	Safety Evaluation of Dexmedetomidine for EBUS-TBNA
NCT01741506	PHASE4	COMPLETED	Coagulation Profile in Patients Undergoing Video Assisted Thorascopic Surgery (VATS) for Lung Cancer
NCT02246023	PHASE4	COMPLETED	Fractionated Versus Target-controlled Propofol Administration in Bronchoscopy
NCT02275702	PHASE4	COMPLETED	Randomized Study of Preoperative Dexamethasone for Quality of Recovery in VATS Lung Resection Patients
NCT02346318	PHASE4	UNKNOWN	The Randomized Controlled Clinical Trial of Kushen Injection
NCT02476526	PHASE4	COMPLETED	Safety of Low Dose IV Contrast CT Scanning in Chronic Kidney Disease
NCT02490059	PHASE4	COMPLETED	Ultrathin Bronchoscopy for Solitary Pulmonary Nodules
NCT02504801	PHASE4	UNKNOWN	Efficacy of Nebulized Pulmicort Respules in Primary Lung Cancer Patients With COPD
NCT02869789	PHASE4	COMPLETED	An Investigational Immuno-therapy Study for Safety of Nivolumab in Combination With Ipilimumab to Treat Advanced Cancers
NCT03302221	PHASE4	WITHDRAWN	Regional Haemodynamic Changes in Radial Artery Assessment With Continuous Pulsed-wave Doppler Ultrasound
NCT03313544	PHASE4	UNKNOWN	Evolution of the Heart Function When Monitoring Immunotherapies Anti-cancerous Inhibiting PD-1
NCT03394222	PHASE4	COMPLETED	Effect of Preoperative Budesonide Inhalation on Arterial Blood Oxygenation and Intrapulmonary Shunt During OLV
NCT03570645	PHASE4	COMPLETED	Comparison of the Duration of Ropivacaine Combined With Dexmedetomidine or Dexamethasone on Paravertebral Block
NCT03571126	PHASE4	UNKNOWN	Olanzapine for the Prevention and Treatment of Nausea and Vomiting Induced by Chemotherapy of Lung Cancer
NCT03642457	PHASE4	TERMINATED	Efficacy Between Serratus Plane Block And Local Infiltration In Vats
NCT04145570	PHASE4	COMPLETED	A Single-Dose,ComparativeBioavailability Study ofTwo Formulations ofErlotinib150mgTabletsunderFastingConditions
NCT04155008	PHASE4	TERMINATED	Nutrition and Pharmacological Algorithm for Oncology Patients Study
NCT04613284	PHASE4	UNKNOWN	Rh-Endostatin Combined With CCRT(50 Gy) Followed by Durvalumab Maintenance for the Treatment of Specific Phase III NSCLC
NCT05463913	PHASE4	RECRUITING	Lung Nodule Detection Using Ultra-long FOV PET/CT
NCT05521789	PHASE4	RECRUITING	Erector Spinae Block for Thoracic Surgery
NCT05525338	PHASE4	RECRUITING	Comparison of Standard Dose Alectinib to Alectinib in Adjusted Dose Based on Alectinib Bloodlevels
NCT05663242	PHASE4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Lung Tumors and Its Mechanism of Action
NCT05926336	PHASE4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Tumors and Its Mechanism of Action
NCT06105801	PHASE4	RECRUITING	EBUS-TBNA vs Transbronchial Mediastinal Cryobiopsy for Adequacy of Next Generation Sequencing
NCT06276933	PHASE4	NOT_YET_RECRUITING	A Study of Camrelizumab Combined With Chemotherapy ± Thalidomide in First-line Treatment of Patients With Advanced Non-small Cell Lung Cancer (NSCLC)
NCT06646471	PHASE4	RECRUITING	PROspective Master-protocol for Evaluation of Systemic THErapeutics in Elderly With Thoracic Malignancies
NCT07405086	PHASE4	RECRUITING	Morning Versus Afternoon Administration of Immunotherapy for the Treatment of Advanced or Metastatic Solid Tumors, The Knight SHIFT Study
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00719017	PHASE4	UNKNOWN	Upper Vaginectomy Versus Brachytherapy in Patients With Early Stage Endometrial Cancer Treated With Laparoscopic Surgery
NCT02543710	PHASE4	RECRUITING	Biomarker Guided Treatment in Gynaecological Cancer