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HCK proto-oncogene, Src family tyrosine kinase

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Target id: 2032

Nomenclature: HCK proto-oncogene, Src family tyrosine kinase

Abbreviated Name: Hck

Family: Src family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 526 20q11.21 HCK HCK proto-oncogene, Src family tyrosine kinase
Mouse - 524 2 75.41 cM Hck hemopoietic cell kinase
Rat - 524 3q41 Hck HCK proto-oncogene, Src family tyrosine kinase
Previous and Unofficial Names Click here for help
Bmk | JTK9 | p56Hck | hemopoietic cell kinase | HCK proto-oncogene
Database Links Click here for help
Alphafold P08631 (Hs), P08103 (Mm), P50545 (Rn)
BRENDA 2.7.10.2
CATH/Gene3D 3.30.505.10
ChEMBL Target CHEMBL3234 (Hs)
Ensembl Gene ENSG00000101336 (Hs), ENSMUSG00000003283 (Mm), ENSRNOG00000009331 (Rn)
Entrez Gene 3055 (Hs), 15162 (Mm), 25734 (Rn)
Human Protein Atlas ENSG00000101336 (Hs)
KEGG Enzyme 2.7.10.2
KEGG Gene hsa:3055 (Hs), mmu:15162 (Mm), rno:25734 (Rn)
OMIM 142370 (Hs)
Pharos P08631 (Hs)
RefSeq Nucleotide NM_001172129 (Hs), NM_010407 (Mm), NM_013185 (Rn)
RefSeq Protein NP_002101 (Hs), NP_034537 (Mm), NP_037317 (Rn)
SynPHARM 80998 (in complex with PP121)
UniProtKB P08631 (Hs), P08103 (Mm), P50545 (Rn)
Wikipedia HCK (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  CRYSTAL STRUCTURE OF HCK IN COMPLEX WITH A SRC FAMILY-SELECTIVE TYROSINE KINASE INHIBITOR
PDB Id:  1QCF
Resolution:  2.0Å
Species:  Human
References:  12
Image of receptor 3D structure from RCSB PDB
Description:  SRC FAMILY KINASE HCK SH3 DOMAIN
PDB Id:  1BU1
Resolution:  2.6Å
Species:  Human
References:  3
Enzyme Reaction Click here for help
EC Number: 2.7.10.2

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
compound 2 [PMID: 15546730] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.7 pIC50 7
⤷ pIC50 8.7 (IC50 2x10-9 M) [7]
eCF506 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.6 pIC50 9
⤷ pIC50 8.6 (IC50 2.8x10-9 M) [9]
PP121 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.1 pIC50 2
⤷ pIC50 8.1 (IC50 8x10-9 M) [2]
pexmetinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.6 pIC50 4
⤷ pIC50 7.6 (IC50 2.6x10-8 M) [4]
ibrutinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.5 pIC50 6
⤷ pIC50 7.5 (IC50 2.9x10-8 M) [6]
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: 8,13
Key to terms and symbols Click column headers to sort
Target used in screen: HCK
Ligand Sp. Type Action Value Parameter
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 9.5 pKd
PD-173955 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.5 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.5 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.8 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.7 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.8 pKd
PP-242 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.7 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.6 pKd
vandetanib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.4 pKd
nilotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.4 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: 1,10
Key to terms and symbols Click column headers to sort
Target used in screen: Hck (activated)/nd
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
TWS119 Small molecule or natural product Hs Inhibitor Inhibition -3.0 -1.0
GSK-3 inhibitor IX Small molecule or natural product Hs Inhibitor Inhibition 1.0 2.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.0 3.0
Lck inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.0 -2.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 1.0 4.0
GSK-3 inhibitor X Small molecule or natural product Hs Inhibitor Inhibition 3.0 -1.0
tivozanib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 5.0 6.0
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 8.0 7.0
Flt-3 inhibitor II Small molecule or natural product Hs Inhibitor Inhibition 8.0 3.0
indirubin-3'-monoxime Small molecule or natural product Hs Inhibitor Inhibition 8.0 1.0
Target used in screen: Hck/HCK
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 0.8
Lck inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 2.2 2.0 1.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 3.3 1.5 2.0
PDGF RTK inhibitor Small molecule or natural product Hs Inhibitor Inhibition 4.9 7.0 1.0
TWS119 Small molecule or natural product Hs Inhibitor Inhibition 6.7 4.0 1.0
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 11.9
K-252a Small molecule or natural product Hs Inhibitor Inhibition 13.2 3.0 1.0
GSK-3 inhibitor IX Small molecule or natural product Hs Inhibitor Inhibition 13.3 6.0 1.0
Src kinase inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 13.5 4.0 5.0
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 14.9 7.0 5.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
Hck is thought to be involved in neutrophil migration, potentially via binding to intergrins [5].
Cell Type Associations
Immuno Cell Type:  Granulocytes
Cell Ontology Term:   eosinophil (CL:0000771)
neutrophil (CL:0000775)
References:  11
Immuno Cell Type:  Dendritic cells
References:  11
Immuno Cell Type:  Macrophages & monocytes
Cell Ontology Term:   macrophage (CL:0000235)
monocyte (CL:0000576)
References:  11
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling

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. Apsel B, Blair JA, Gonzalez B, Nazif TM, Feldman ME, Aizenstein B, Hoffman R, Williams RL, Shokat KM, Knight ZA. (2008) Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat Chem Biol, 4 (11): 691-9. [PMID:18849971]

3. Arold S, O'Brien R, Franken P, Strub MP, Hoh F, Dumas C, Ladbury JE. (1998) RT loop flexibility enhances the specificity of Src family SH3 domains for HIV-1 Nef. Biochemistry, 37 (42): 14683-91. [PMID:9778343]

4. Bachegowda L, Morrone K, Winski SL, Mantzaris I, Bartenstein M, Ramachandra N, Giricz O, Sukrithan V, Nwankwo G, Shahnaz S et al.. (2016) Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia. Cancer Res, 76 (16): 4841-4849. [PMID:27287719]

5. Baruzzi A, Iacobucci I, Soverini S, Lowell CA, Martinelli G, Berton G. (2010) c-Abl and Src-family kinases cross-talk in regulation of myeloid cell migration. FEBS Lett, 584 (1): 15-21. [PMID:19903482]

6. 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]

7. Chen P, Norris D, Das J, Spergel SH, Wityak J, Leith L, Zhao R, Chen BC, Pitt S, Pang S et al.. (2004) Discovery of novel 2-(aminoheteroaryl)-thiazole-5-carboxamides as potent and orally active Src-family kinase p56(Lck) inhibitors. Bioorg Med Chem Lett, 14 (24): 6061-6. [PMID:15546730]

8. 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]

9. Fraser C, Dawson JC, Dowling R, Houston DR, Weiss JT, Munro AF, Muir M, Harrington L, Webster SP, Frame MC et al.. (2016) Rapid Discovery and Structure-Activity Relationships of Pyrazolopyrimidines That Potently Suppress Breast Cancer Cell Growth via SRC Kinase Inhibition with Exceptional Selectivity over ABL Kinase. J Med Chem, 59 (10): 4697-710. [PMID:27115835]

10. 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]

11. Lowell CA. (2004) Src-family kinases: rheostats of immune cell signaling. Mol Immunol, 41 (6-7): 631-43. [PMID:15220000]

12. Schindler T, Sicheri F, Pico A, Gazit A, Levitzki A, Kuriyan J. (1999) Crystal structure of Hck in complex with a Src family-selective tyrosine kinase inhibitor. Mol Cell, 3 (5): 639-48. [PMID:10360180]

13. 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

Src family: HCK proto-oncogene, Src family tyrosine kinase. Last modified on 24/04/2018. Accessed on 15/10/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2032.