v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2

Target id: 2019

Nomenclature: v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2

Abbreviated Name: HER2

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

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 1225 17q11.2-q12 ERBB2 v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2
Mouse 1 1225 11 D Erbb2 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)
Rat 1 1259 10 q32.1 Erbb2 v-erb-b2 avian erythroblastic leukemia viral oncogene 2
Previous and Unofficial Names
CD340
c-erbB2
epidermal growth factor receptor-related protein
Neu oncogene
NEU proto-oncogene
p185neu
Database Links
BRENDA
Ensembl Gene
Entrez Gene
ExplorEnz
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG BRITE Hierarchy
KEGG Gene
OMIM
PhosphoSitePlus
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene
UniProtKB
Wikipedia
Selected 3D Structures
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:  5
Enzyme Reaction
EC Number: 2.7.10.1
Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
EGFR/ErbB-2/ErbB-4 inhibitor Hs Inhibition 8.96 pIC50 9
pIC50 8.96 (IC50 1.1x10-9 M) [9]
AEE788 Hs Inhibition 8.22 pIC50 15
pIC50 8.22 (IC50 6x10-9 M) [15]
mubritinib Hs Inhibition 8.22 pIC50 11
pIC50 8.22 (IC50 6x10-9 M) [11]
Description: Measuring tyrosine phosphorylation of HER2 in human bladder cancer cell lineT24.
lapatinib Hs Inhibition 8.0 pIC50 13
pIC50 8.0 (IC50 9.8x10-9 M) [13]
CP-724714 Hs Inhibition 7.92 pIC50 8
pIC50 7.92 (IC50 1.2x10-8 M) [8]
sapitinib Hs Inhibition 7.85 pIC50 4
pIC50 7.85 (IC50 1.4x10-8 M) [4]
BMS-690514 Hs Inhibition 7.72 pIC50 10
pIC50 7.72 (IC50 1.9x10-8 M) [10]
BMS-599626 Hs Inhibition 7.49 pIC50 7
pIC50 7.49 (IC50 2.2x10-8 M) [7]
dacomitinib Hs Inhibition 7.34 pIC50 3
pIC50 7.34 (IC50 4.6x10-8 M) [3]
neratinib Hs Inhibition 7.23 pIC50 12
pIC50 7.23 (IC50 5.9x10-8 M) [12]
Description: Inhibition of autophosphorylation of the cytoplasmic domain of the RTK in a cell free system.
falnidamol Hs Inhibition 5.47 pIC50 14
pIC50 5.47 (IC50 3.4x10-6 M) [14]
Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Affinity Units Reference
trastuzumab Hs Inhibition - -
pertuzumab Hs Inhibition - -
DiscoveRx KINOMEscan® screen
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: 6,16

Key to terms and symbols Click column headers to sort
Target used in screen: ERBB2
Ligand Sp. Type Action Affinity Units
afatinib Hs Inhibitor Inhibition 8.3 pKd
neratinib Hs Inhibitor Inhibition 8.22 pKd
lapatinib Hs Inhibitor Inhibition 8.15 pKd
canertinib Hs Inhibitor Inhibition 7.25 pKd
staurosporine Hs Inhibitor Inhibition 6.72 pKd
TG-100-115 Hs Inhibitor Inhibition 6.36 pKd
NVP-TAE684 Hs Inhibitor Inhibition 6.27 pKd
foretinib Hs Inhibitor Inhibition 6.24 pKd
masitinib Hs Inhibitor Inhibition 5.92 pKd
dasatinib Hs Inhibitor Inhibition 5.85 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen
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 Hs Inhibitor Inhibition 2.4
lapatinib Hs Inhibitor Inhibition 9.6
compound 56 [PMID:8568816] Hs Inhibitor Inhibition 13.8
PDK1/Akt/Flt dual pathway inhibitor Hs Inhibitor Inhibition 22.2
AG1478 Hs Inhibitor Inhibition 22.5
PD 158780 Hs Inhibitor Inhibition 28.9
Src kinase inhibitor I Hs Inhibitor Inhibition 29.5
bosutinib Hs Inhibitor Inhibition 32.9
JAK3 inhibitor II Hs Inhibitor Inhibition 33.1
PD 174265 Hs Inhibitor Inhibition 34.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology
Disease:  Adenocarcinoma of lung, somatic
OMIM:  211980
Disease:  Gastric cancer, somatic
OMIM:  613659
Disease:  Glioblastoma, somatic
OMIM:  137800
Disease:  Ovarian cancer
OMIM:  167000

References

Show »

1. Aertgeerts K, Skene R, Yano J, Sang BC, Zou H, Snell G, Jennings A, Iwamoto K, Habuka N, Hirokawa A et al.. (2011) Structural analysis of the mechanism of inhibition and allosteric activation of the kinase domain of HER2 protein. J. Biol. Chem.286 (21): 18756-65. [PMID:21454582]

2. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol.29 (11): 1039-45. [PMID:22037377]

3. Barf T, Kaptein A. (2012) Irreversible protein kinase inhibitors: balancing the benefits and risks. J. Med. Chem.55 (14): 6243-62. [PMID:22621397]

4. Barlaam B, Anderton J, Ballard P, Bradbury RH, Hennequin LF, Hickinson DM, Kettle JG, Kirk G, Klinowska T, Lambert-van der Brempt C et al.. (2013) Discovery of AZD8931, an Equipotent, Reversible Inhibitor of Signaling by EGFR, HER2, and HER3 Receptors. ACS Med Chem Lett4 (8): 742-6. [PMID:24900741]

5. Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW, Leahy DJ. (2003) Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature421 (6924): 756-60. [PMID:12610629]

6. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol.29 (11): 1046-51. [PMID:22037378]

7. Gavai AV, Fink BE, Fairfax DJ, Martin GS, Rossiter LM, Holst CL, Kim SH, Leavitt KJ, Mastalerz H, Han WC et al.. (2009) Discovery and preclinical evaluation of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid, (3S)-3-morpholinylmethyl ester (BMS-599626), a selective and orally efficacious inhibitor of human epidermal growth factor receptor 1 and 2 kinases. J. Med. Chem.52 (21): 6527-30. [PMID:19821562]

8. Gundla R, Kazemi R, Sanam R, Muttineni R, Sarma JA, Dayam R, Neamati N. (2008) Discovery of novel small-molecule inhibitors of human epidermal growth factor receptor-2: combined ligand and target-based approach. J. Med. Chem.51 (12): 3367-77. [PMID:18500794]

9. Klutchko SR, Zhou H, Winters RT, Tran TP, Bridges AJ, Althaus IW, Amato DM, Elliott WL, Ellis PA, Meade MA et al.. (2006) Tyrosine kinase inhibitors. 19. 6-Alkynamides of 4-anilinoquinazolines and 4-anilinopyrido[3,4-d]pyrimidines as irreversible inhibitors of the erbB family of tyrosine kinase receptors. J. Med. Chem.49 (4): 1475-85. [PMID:16480284]

10. Marathe P, Tang Y, Sleczka B, Rodrigues D, Gavai A, Wong T, Christopher L, Zhang H. (2010) Preclinical pharmacokinetics and in vitro metabolism of BMS-690514, a potent inhibitor of EGFR and VEGFR2. J Pharm Sci99 (8): 3579-93. [PMID:20166197]

11. Nagasawa J, Mizokami A, Koshida K, Yoshida S, Naito K, Namiki M. (2006) Novel HER2 selective tyrosine kinase inhibitor, TAK-165, inhibits bladder, kidney and androgen-independent prostate cancer in vitro and in vivo. Int. J. Urol.13 (5): 587-92. [PMID:16771730]

12. Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J, Hallett WA, Johnson BD, Nilakantan R, Overbeek E et al.. (2004) Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res.64 (11): 3958-65. [PMID:15173008]

13. Rusnak DW, Lackey K, Affleck K, Wood ER, Alligood KJ, Rhodes N, Keith BR, Murray DM, Knight WB, Mullin RJ et al.. (2001) The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol. Cancer Ther.1 (2): 85-94. [PMID:12467226]

14. Solca FF, Baum A, Langkopf E, Dahmann G, Heider KH, Himmelsbach F, van Meel JC. (2004) Inhibition of epidermal growth factor receptor activity by two pyrimidopyrimidine derivatives. J. Pharmacol. Exp. Ther.311 (2): 502-9. [PMID:15199094]

15. Traxler P, Allegrini PR, Brandt R, Brueggen J, Cozens R, Fabbro D, Grosios K, Lane HA, McSheehy P, Mestan J et al.. (2004) AEE788: a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res.64 (14): 4931-41. [PMID:15256466]

16. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol.17 (11): 1241-9. [PMID:21095574]

How to cite this page

Type I RTKs: ErbB (epidermal growth factor) receptor family: v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2. Last modified on 05/11/2014. Accessed on 18/12/2014. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2019.