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erb-b2 receptor tyrosine kinase 4

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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

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 1308 2q34 ERBB4 erb-b2 receptor tyrosine kinase 4
Mouse 1 1308 1 33.8 cM Erbb4 erb-b2 receptor tyrosine kinase 4
Rat 1 1308 9q32-q33 Erbb4 erb-b2 receptor tyrosine kinase 4
Previous and Unofficial Names Click here for help
Her4 | v-erb-b2 avian erythroblastic leukemia viral oncogene 4 | v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4
Database Links Click here for help
Alphafold Q15303 (Hs), Q61527 (Mm), Q62956 (Rn)
BRENDA 2.7.10.1
CATH/Gene3D 3.80.20.20
ChEMBL Target CHEMBL3009 (Hs)
DrugBank Target Q15303 (Hs)
Ensembl Gene ENSG00000178568 (Hs), ENSMUSG00000062209 (Mm), ENSRNOG00000014248 (Rn)
Entrez Gene 2066 (Hs), 13869 (Mm), 59323 (Rn)
Human Protein Atlas ENSG00000178568 (Hs)
KEGG Enzyme 2.7.10.1
KEGG Gene hsa:2066 (Hs), mmu:13869 (Mm), rno:59323 (Rn)
OMIM 600543 (Hs)
Orphanet ORPHA370064 (Hs)
Pharos Q15303 (Hs)
RefSeq Nucleotide NM_001042599 (Hs), NM_010154 (Mm), NM_021687 (Rn)
RefSeq Protein NP_001036064 (Hs), NP_034284 (Mm), NP_067719 (Rn)
UniProtKB Q15303 (Hs), Q61527 (Mm), Q62956 (Rn)
Wikipedia ERBB4 (Hs)
Selected 3D Structures Click here for help
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:  17
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the ErbB4 kinase
PDB Id:  3BCE
Resolution:  2.5Å
Species:  Human
References:  13
Enzyme Reaction Click here for help
EC Number: 2.7.10.1
Natural/Endogenous Ligands Click here for help
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 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
WZ4002 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.6 pKd 19
⤷ pKd 7.6 (Kd 2.8x10-8 M) [19]
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 9.3 pIC50 9
⤷ pIC50 9.3 (IC50 5x10-10 M) [9]
allitinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.1 pIC50 18
⤷ pIC50 9.1 (IC50 8x10-10 M) [18]
pirotinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.7 pIC50 8
⤷ pIC50 8.7 (IC50 1.9x10-9 M) [8]
compound 38 [PMID: 24915291] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.5 pIC50 11
⤷ pIC50 8.5 (IC50 3.3x10-9 M) [11]
ibrutinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.5 pIC50 4
⤷ pIC50 8.5 (IC50 3.4x10-9 M) [4]
acalabrutinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.8 pIC50 4
⤷ pIC50 7.8 (IC50 1.6x10-8 M) [4]
poziotinib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.6 pIC50 12
⤷ pIC50 7.6 (IC50 2.35x10-8 M) [12]
AEE788 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.6 pIC50 15
⤷ pIC50 7.6 (IC50 2.6x10-8 M) [15]
compound 9 [PMID: 26006010] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.2 pIC50 3
⤷ pIC50 7.2 (IC50 6.5x10-8 M) [3]
dacomitinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.1 pIC50 2
⤷ pIC50 7.1 (IC50 7.4x10-8 M) [2]
BMS-599626 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.7 pIC50 7
⤷ pIC50 6.7 (IC50 1.9x10-7 M) [7]
tucatinib Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inhibition 6.5 pIC50 10
⤷ pIC50 6.5 (IC50 3.1x10-7 M) [10]
Description: Inhibition of enzyme activity in a biochemical assay.
xiliertinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.2 pIC50 14
⤷ pIC50 6.2 (IC50 7.05x10-7 M) [14]
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: 5,16
Key to terms and symbols Click column headers to sort
Target used in screen: ERBB4
Ligand Sp. Type Action Value Parameter
neratinib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 8.6 pKd
afatinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 8.2 pKd
canertinib Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 8.2 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.6 pKd
lapatinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.3 pKd
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.3 pKd
erlotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.6 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.6 pKd
gefitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.4 pKd
barasertib-hQPA Small molecule or natural product Ligand has a PDB structure 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 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: 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 Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 1.5
EGFR/ErbB-2/ErbB-4 inhibitor Small molecule or natural product Hs Inhibitor Inhibition 1.9 16.0 14.0
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 4.0
Src kinase inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.8 -3.0 -5.0
EGFR/ErbB-2 inhibitor Small molecule or natural product Hs Inhibitor Inhibition 9.2 -1.0 -3.0
lapatinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 11.2
Lck inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 11.9 0.0 -4.0
gefitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 24.2
JAK3 inhibitor II Small molecule or natural product Hs Inhibitor Inhibition 29.1 16.0 -1.0
compound 56 [PMID: 8568816] Small molecule or natural product Hs Inhibitor Inhibition 34.3 10.0 -4.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immuno Process Associations
Immuno Process:  Tissue repair
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Amyotrophic lateral sclerosis 19; ALS19
Synonyms: Amyotrophic lateral sclerosis [Orphanet: ORPHA803]
OMIM: 615515
Orphanet: ORPHA803

References

Show »

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. Huang Z, Dong Y. (2012) Quinazoline derivatives substituted by aniline, preparation method and use thereof. Patent number: WO2012027960A1. Assignee: Shandong Xuanzhu Pharma Co Ltd. Priority date: 30/08/2011. Publication date: 30/03/2012.

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. Kulukian A, Lee P, Taylor J, Rosler R, de Vries P, Watson D, Forero-Torres A, Peterson S. (2020) Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models. Mol Cancer Ther, 19 (4): 976-987. [PMID:32241871]

11. 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]

12. 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]

13. 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]

14. 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]

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]

17. 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 USA, 105 (8): 2773-8. [PMID:18287036]

18. 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]

19. 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 19/04/2023. Accessed on 13/10/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1799.