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erb-b2 receptor tyrosine kinase 2

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Target not currently curated in GtoImmuPdb

Target id: 2019

Nomenclature: erb-b2 receptor tyrosine kinase 2

Abbreviated Name: HER2

Family: Type I RTKs: ErbB (epidermal growth factor) receptor family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 1255 17q12 ERBB2 erb-b2 receptor tyrosine kinase 2
Mouse 1 1256 11 D Erbb2 erb-b2 receptor tyrosine kinase 2
Rat 1 1257 10q31 Erbb2 erb-b2 receptor tyrosine kinase 2
Previous and Unofficial Names Click here for help
CD340 | c-erbB2 | epidermal growth factor receptor-related protein | Neu oncogene | NEU proto-oncogene | p185neu | v-erb-b2 avian erythroblastic leukemia viral oncogene 2 | v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2
Database Links Click here for help
Alphafold P04626 (Hs), P70424 (Mm), P06494 (Rn)
BRENDA 2.7.10.1
CATH/Gene3D 3.80.20.20
ChEMBL Target CHEMBL1824 (Hs), CHEMBL2311234 (Mm), CHEMBL3848 (Rn)
DrugBank Target P04626 (Hs)
Ensembl Gene ENSG00000141736 (Hs), ENSMUSG00000062312 (Mm), ENSRNOG00000006450 (Rn)
Entrez Gene 2064 (Hs), 13866 (Mm), 24337 (Rn)
Human Protein Atlas ENSG00000141736 (Hs)
KEGG Enzyme 2.7.10.1
KEGG Gene hsa:2064 (Hs), mmu:13866 (Mm), rno:24337 (Rn)
OMIM 164870 (Hs)
Pharos P04626 (Hs)
RefSeq Nucleotide NM_001005862 (Hs), NM_010194 (Mm), NM_017003 (Rn)
RefSeq Protein NP_001005862 (Hs), NP_034324 (Mm), NP_058699 (Rn)
UniProtKB P04626 (Hs), P70424 (Mm), P06494 (Rn)
Wikipedia ERBB2 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the kinase domain of human HER2 (ERBB2).
PDB Id:  3PP0
Resolution:  2.25Å
Species:  Human
References:  1
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of extracellular domain of human HER2 complexed with Herceptin Fab.
PDB Id:  1N8Z
Ligand:  trastuzumab
Resolution:  2.52Å
Species:  Human
References:  8
Enzyme Reaction Click here for help
EC Number: 2.7.10.1

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
neratinib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.2 pKd 10
⤷ pKd 8.2 (Kd 6x10-9 M) [10]
lapatinib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.1 pKd 10
⤷ pKd 8.1 (Kd 7x10-9 M) [10]
EGFR/ErbB-2/ErbB-4 inhibitor Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 9.0 pIC50 19
⤷ pIC50 9.0 (IC50 1.1x10-9 M) [19]
allitinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.5 pIC50 36
⤷ pIC50 8.5 (IC50 3x10-9 M) [36]
poziotinib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.3 pIC50 27
⤷ pIC50 8.3 (IC50 5.3x10-9 M) [27]
mubritinib Small molecule or natural product Primary target of this compound Hs Inhibition 8.2 pIC50 26
⤷ pIC50 8.2 (IC50 6x10-9 M) [26]
Description: Measuring tyrosine phosphorylation of HER2 in human bladder cancer cell lineT24.
AEE788 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.2 pIC50 32
⤷ pIC50 8.2 (IC50 6x10-9 M) [32]
ibrutinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.2 pIC50 5
⤷ pIC50 8.2 (IC50 6.4x10-9 M) [5]
pirotinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.2 pIC50 15
⤷ pIC50 8.2 (IC50 6.5x10-9 M) [15]
tucatinib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.2 pIC50 20
⤷ pIC50 8.2 (IC50 6.9x10-9 M) [20]
Description: Inhibition of enzyme activity in a biochemical assay.
compound 38 [PMID: 24915291] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.1 pIC50 23
⤷ pIC50 8.1 (IC50 7x10-9 M) [23]
tuxobertinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.0 – 8.3 pIC50 11
⤷ pIC50 8.0 – 8.3 (IC50 1x10-8 – 5x10-9 M) [11]
Description: Inhibition of WT HER2 kinase activity
selatinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.1 pIC50 38
⤷ pIC50 8.1 (IC50 8.5x10-9 M) [38]
canertinib Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.1 pIC50 30
⤷ pIC50 8.1 (IC50 9x10-9 M) [30]
Description: Inhibition of ErbB2 autophosphorylation
lapatinib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.0 pIC50 29
⤷ pIC50 8.0 (IC50 9.8x10-9 M) [29]
mifanertinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.9 pIC50 37
⤷ pIC50 7.9 (IC50 1.17x10-8 M) [37]
CP-724714 Small molecule or natural product Primary target of this compound Hs Inhibition 7.9 pIC50 14
⤷ pIC50 7.9 (IC50 1.2x10-8 M) [14]
zongertinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.9 pIC50 33
⤷ pIC50 7.9 (IC50 1.3x10-8 M) [33]
Description: Inhibition of phosphorylation of HER2 YMVA mutation
afatinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.8 pIC50 21
⤷ pIC50 7.8 (IC50 1.4x10-8 M) [21]
sapitinib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.8 pIC50 4
⤷ pIC50 7.8 (IC50 1.4x10-8 M) [4]
tesevatinib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.8 pIC50 13
⤷ pIC50 7.8 (IC50 1.6x10-8 M) [13]
CUDC-101 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.8 pIC50 6
⤷ pIC50 7.8 (IC50 1.57x10-8 M) [6]
BMS-690514 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.7 pIC50 24
⤷ pIC50 7.7 (IC50 1.9x10-8 M) [24]
BI-4142 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.1 – 8.0 pIC50 34
⤷ pIC50 8.0 (IC50 1x10-8 M) [34]
Description: Inhibition of auto-phosphorylation of HER2YVMA overexpressed in HEK293 cells
pIC50 7.1 (IC50 8.2x10-8 M) [34]
Description: Cellular assay: inhibition of proliferation of NCI-H2170 cells expressing HER2YVMA
BMS-599626 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.5 pIC50 12
⤷ pIC50 7.5 (IC50 2.2x10-8 M) [12]
pyrotinib Small molecule or natural product Approved drug Click here for species-specific activity table Hs Irreversible inhibition 7.4 pIC50 22
⤷ pIC50 7.4 (IC50 3.8x10-8 M) [22]
dacomitinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.3 pIC50 3
⤷ pIC50 7.3 (IC50 4.6x10-8 M) [3]
neratinib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.2 pIC50 28
⤷ pIC50 7.2 (IC50 5.9x10-8 M) [28]
Description: Inhibition of autophosphorylation of the cytoplasmic domain of the RTK in a cell free system.
EGFR/ErbB-2 inhibitor Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.1 pIC50 9
⤷ pIC50 7.1 (IC50 7.9x10-8 M) [9]
acalabrutinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition <6.0 pIC50 5
⤷ pIC50 <6.0 (IC50 >1x10-6 M) [5]
falnidamol Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.5 pIC50 31
⤷ pIC50 5.5 (IC50 3.4x10-6 M) [31]
Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
MM-111 Peptide Primary target of this compound Click here for species-specific activity table Hs Binding 9.5 pKd 25
⤷ pKd 9.5 (Kd 3x10-10 M) [25]
pertuzumab Peptide Approved drug Primary target of this compound Hs Inhibition >8.0 pIC50 17
⤷ pIC50 >8.0 (IC50 <1x10-8 M) [17]
Description: Preferred value for inhibition of heregulin β1 binding to MCF7 cells.
trastuzumab Peptide Approved drug Primary target of this compound Hs Inhibition - -
⤷
margetuximab Peptide Approved drug Primary target of this compound Hs Binding - - 16
⤷ [16]
Antibody Comments
An anti-ERBB2/CD3e Triomab® called ertumaxomab (Rexomun®) has demonstrated antitumour efficacy against HER2/neu low-expressing breast tumours that are resistant to trastuzumab [18]. Development of ertumaxomab was not progressed beyond Phase 2 for business reasons. No safety issues had been apparent. See the entry for catumaxomab for full details of Triomab® mechanism of action.
Dragonfly Therapeutics are developing agents, using a platform called TriNKETTM (an abbreviation for tri-specific natural killer cell engagement therapies), that simultaneously engage a surface protein on target cells (e.g. cancer cells) and an as yet undisclosed natural killer (NK) cell protein so as to activate and redirect NK cells of the innate and adaptive immune system to destroy cancers. A patent held by Dragonfly Therapeutics suggests that one of the NK cell targets they are interested in is NKG2D (KLRK1; P26718) [7]. Their most advanced candidate (as of November 2019) is DF1001, a HER2-targeting TriNKETTM that has begun Phase 1/2 evaluation in HER2 +ve solid tumours (see NCT04143711). TriNKETTM therapeutics have the potential to treat autoimmune disease in addition to cancer.
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 10,35
Key to terms and symbols Click column headers to sort
Target used in screen: ERBB2
Ligand Sp. Type Action Value Parameter
afatinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 8.3 pKd
neratinib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 8.2 pKd
lapatinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 8.1 pKd
canertinib Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 7.3 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.7 pKd
TG-100-115 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.4 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.3 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.2 pKd
masitinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 5.9 pKd
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 5.8 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: ...2
Key to terms and symbols Click column headers to sort
Target used in screen: nd/ERBB2(HER2)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
EGFR/ErbB-2/ErbB-4 inhibitor Small molecule or natural product Hs Inhibitor Inhibition 2.4
lapatinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 9.6
compound 56 [PMID: 8568816] Small molecule or natural product Hs Inhibitor Inhibition 13.8
PDK1/Akt/Flt dual pathway inhibitor Small molecule or natural product Hs Inhibitor Inhibition 22.2
AG1478 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 22.5
PD 158780 Small molecule or natural product Hs Inhibitor Inhibition 28.9
Src kinase inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 29.5
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 32.9
JAK3 inhibitor II Small molecule or natural product Hs Inhibitor Inhibition 33.1
PD 174265 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 34.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immuno Process Associations
Immuno Process:  T cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Immune system development
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Gastric cancer
Synonyms: Stomach cancer
Disease Ontology: DOID:10534
OMIM: 613659
Disease:  Glioblastoma
Synonyms: Glioblastoma multiforme
Glioma susceptibility 1; GLM1 [OMIM: 137800]
Disease Ontology: DOID:3068
OMIM: 137800
Orphanet: ORPHA360
Disease:  Lung cancer
Disease Ontology: DOID:1324
OMIM: 211980
Role:  Mutations in ERBB2 are associated with lung adenocarcinoma
Disease:  Ovarian cancer
Disease Ontology: DOID:2394
OMIM: 167000

References

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Type I RTKs: ErbB (epidermal growth factor) receptor family: erb-b2 receptor tyrosine kinase 2. Last modified on 19/04/2023. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2019.