erb-b2 receptor tyrosine kinase 4 | Type I RTKs: ErbB (epidermal growth factor) receptor family | IUPHAR/BPS Guide to PHARMACOLOGY

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erb-b2 receptor tyrosine kinase 4

Target not currently curated in GtoImmuPdb

Target id: 1799

Nomenclature: erb-b2 receptor tyrosine kinase 4

Abbreviated Name: HER4

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 1292 2q33.3-q34 ERBB4 erb-b2 receptor tyrosine kinase 4
Mouse 1 1292 1 Erbb4 erb-b2 receptor tyrosine kinase 4
Rat 1 1308 9q32 Erbb4 erb-b2 receptor tyrosine kinase 4
Previous and Unofficial Names
Her4 | v-erb-b2 avian erythroblastic leukemia viral oncogene 4 | v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  ErbB4 kinase domain complexed with a thienopyrimidine inhibitor
PDB Id:  2R4B
Resolution:  2.4Å
Species:  Human
References:  15
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the ErbB4 kinase
PDB Id:  3BCE
Resolution:  2.5Å
Species:  Human
References:  11
Enzyme Reaction
EC Number: 2.7.10.1
Natural/Endogenous Ligands
betacellulin {Sp: Human}
epiregulin {Sp: Human}
HB-EGF {Sp: Human}
neuregulin-1 {Sp: Human}
neuregulin-2 {Sp: Human}
neuregulin-3 {Sp: Human}
neuregulin-4 {Sp: Human}

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
WZ4002 Hs Inhibition 7.6 pKd 17
pKd 7.6 (Kd 2.8x10-8 M) [17]
EGFR/ErbB-2/ErbB-4 inhibitor Hs Inhibition 9.3 pIC50 8
pIC50 9.3 (IC50 5x10-10 M) [8]
allitinib Hs Inhibition 9.1 pIC50 16
pIC50 9.1 (IC50 8x10-10 M) [16]
compound 38 [PMID: 24915291] Hs Inhibition 8.5 pIC50 9
pIC50 8.5 (IC50 3.3x10-9 M) [9]
ibrutinib Hs Inhibition 8.5 pIC50 4
pIC50 8.5 (IC50 3.4x10-9 M) [4]
acalabrutinib Hs Inhibition 7.8 pIC50 4
pIC50 7.8 (IC50 1.6x10-8 M) [4]
poziotinib Hs Inhibition 7.6 pIC50 10
pIC50 7.6 (IC50 2.35x10-8 M) [10]
AEE788 Hs Inhibition 7.6 pIC50 13
pIC50 7.6 (IC50 2.6x10-8 M) [13]
compound 9 [PMID: 26006010] Hs Inhibition 7.2 pIC50 3
pIC50 7.2 (IC50 6.5x10-8 M) [3]
dacomitinib Hs Inhibition 7.1 pIC50 2
pIC50 7.1 (IC50 7.4x10-8 M) [2]
BMS-599626 Hs Inhibition 6.7 pIC50 7
pIC50 6.7 (IC50 1.9x10-7 M) [7]
theliatinib Hs Inhibition 6.2 pIC50 12
pIC50 6.2 (IC50 7.05x10-7 M) [12]
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: 5,14

Key to terms and symbols Click column headers to sort
Target used in screen: ERBB4
Ligand Sp. Type Action Value Parameter
neratinib Hs Inhibitor Inhibition 8.6 pKd
afatinib Hs Inhibitor Inhibition 8.2 pKd
canertinib Hs Inhibitor Inhibition 8.2 pKd
bosutinib Hs Inhibitor Inhibition 7.6 pKd
lapatinib Hs Inhibitor Inhibition 7.3 pKd
dasatinib Hs Inhibitor Inhibition 7.3 pKd
erlotinib Hs Inhibitor Inhibition 6.6 pKd
NVP-TAE684 Hs Inhibitor Inhibition 6.6 pKd
gefitinib Hs Inhibitor Inhibition 6.4 pKd
barasertib-hQPA Hs Inhibitor Inhibition 6.3 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: 1,6

Key to terms and symbols Click column headers to sort
Target used in screen: ErbB4/ERBB4(HER4)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
bosutinib Hs Inhibitor Inhibition 1.5
EGFR/ErbB-2/ErbB-4 inhibitor Hs Inhibitor Inhibition 1.9 16.0 14.0
dasatinib Hs Inhibitor Inhibition 4.0
Src kinase inhibitor I Hs Inhibitor Inhibition 8.8 -3.0 -5.0
EGFR/ErbB-2 inhibitor Hs Inhibitor Inhibition 9.2 -1.0 -3.0
lapatinib Hs Inhibitor Inhibition 11.2
Lck inhibitor Hs Inhibitor Inhibition 11.9 0.0 -4.0
gefitinib Hs Inhibitor Inhibition 24.2
JAK3 inhibitor II Hs Inhibitor Inhibition 29.1 16.0 -1.0
compound 56 [PMID: 8568816] Hs Inhibitor Inhibition 34.3 10.0 -4.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology
Disease:  Amyotrophic lateral sclerosis 19; ALS19
Synonyms: Amyotrophic lateral sclerosis [Orphanet: ORPHA803]
OMIM: 615515
Orphanet: ORPHA803

References

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1. 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]

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

3. Bradshaw JM, McFarland JM, Paavilainen VO, Bisconte A, Tam D, Phan VT, Romanov S, Finkle D, Shu J, Patel V et al.. (2015) Prolonged and tunable residence time using reversible covalent kinase inhibitors. Nat. Chem. Biol., 11 (7): 525-31. [PMID:26006010]

4. Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR et al.. (2016) Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N. Engl. J. Med., 374 (4): 323-32. [PMID:26641137]

5. 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]

6. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem. J., 451 (2): 313-28. [PMID:23398362]

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. 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]

9. Li X, Zuo Y, Tang G, Wang Y, Zhou Y, Wang X, Guo T, Xia M, Ding N, Pan Z. (2014) Discovery of a series of 2,5-diaminopyrimidine covalent irreversible inhibitors of Bruton's tyrosine kinase with in vivo antitumor activity. J. Med. Chem., 57 (12): 5112-28. [PMID:24915291]

10. Nam HJ, Kim HP, Yoon YK, Hur HS, Song SH, Kim MS, Lee GS, Han SW, Im SA, Kim TY et al.. (2011) Antitumor activity of HM781-36B, an irreversible Pan-HER inhibitor, alone or in combination with cytotoxic chemotherapeutic agents in gastric cancer. Cancer Lett., 302 (2): 155-65. [PMID:21306821]

11. Qiu C, Tarrant MK, Choi SH, Sathyamurthy A, Bose R, Banjade S, Pal A, Bornmann WG, Lemmon MA, Cole PA et al.. (2008) Mechanism of activation and inhibition of the HER4/ErbB4 kinase. Structure, 16 (3): 460-7. [PMID:18334220]

12. Ren Y, Zheng J, Fan S, Wang L, Cheng M, Shi D, Zhang W, Tang R, Yu Y, Jiao L et al.. (2017) Anti-tumor efficacy of theliatinib in esophageal cancer patient-derived xenografts models with epidermal growth factor receptor (EGFR) overexpression and gene amplification. Oncotarget, 8 (31): 50832-50844. [PMID:28881608]

13. 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]

14. 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]

15. Wood ER, Shewchuk LM, Ellis B, Brignola P, Brashear RL, Caferro TR, Dickerson SH, Dickson HD, Donaldson KH, Gaul M et al.. (2008) 6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases. Proc. Natl. Acad. Sci. U.S.A., 105 (8): 2773-8. [PMID:18287036]

16. Xie H, Lin L, Tong L, Jiang Y, Zheng M, Chen Z, Jiang X, Zhang X, Ren X, Qu W et al.. (2011) AST1306, a novel irreversible inhibitor of the epidermal growth factor receptor 1 and 2, exhibits antitumor activity both in vitro and in vivo. PLoS ONE, 6 (7): e21487. [PMID:21789172]

17. Zhou W, Ercan D, Chen L, Yun CH, Li D, Capelletti M, Cortot AB, Chirieac L, Iacob RE, Padera R et al.. (2009) Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature, 462 (7276): 1070-4. [PMID:20033049]

How to cite this page

Type I RTKs: ErbB (epidermal growth factor) receptor family: erb-b2 receptor tyrosine kinase 4. Last modified on 08/02/2019. Accessed on 19/08/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1799.