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BLK proto-oncogene, Src family tyrosine kinase

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 1940

Nomenclature: BLK proto-oncogene, Src family tyrosine kinase

Abbreviated Name: Blk

Family: Src family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 505 8p23.1 BLK BLK proto-oncogene, Src family tyrosine kinase
Mouse - 499 14 33.25 cM Blk B lymphoid kinase
Rat - 499 15p12 Blk BLK proto-oncogene, Src family tyrosine kinase
Previous and Unofficial Names Click here for help
B lymphocyte kinase | p55-Blk | BLK proto-oncogene
Database Links Click here for help
Alphafold P51451 (Hs), P16277 (Mm)
BRENDA 2.7.10.2
CATH/Gene3D 3.30.505.10
ChEMBL Target CHEMBL2250 (Hs), CHEMBL3343 (Mm)
Ensembl Gene ENSG00000136573 (Hs), ENSMUSG00000014453 (Mm), ENSRNOG00000010798 (Rn)
Entrez Gene 640 (Hs), 12143 (Mm), 364403 (Rn)
Human Protein Atlas ENSG00000136573 (Hs)
KEGG Enzyme 2.7.10.2
KEGG Gene hsa:640 (Hs), mmu:12143 (Mm), rno:364403 (Rn)
OMIM 191305 (Hs)
Orphanet ORPHA227384 (Hs)
Pharos P51451 (Hs)
RefSeq Nucleotide NM_001715 (Hs), NM_007549 (Mm), NM_001025751 (Rn)
RefSeq Protein NP_001706 (Hs), NP_031575 (Mm), NP_001020922 (Rn)
UniProtKB P51451 (Hs), P16277 (Mm)
Wikipedia BLK (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  NMR ensemble of BLK SH3 domain
PDB Id:  1BLJ
Resolution:  0.0Å
Species:  Mouse
References:  14
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
ZAK inhibitor 6p Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.7 pKd 21
⤷ pKd 6.7 (Kd 1.9x10-7 M) [21]
WZ4002 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.7 pKd 24
⤷ pKd 6.7 (Kd 2x10-7 M) [24]
ibrutinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 9.3 – 10.0 pIC50 3,12
⤷ pIC50 10.0 (IC50 1x10-10 M) [3]
pIC50 9.3 (IC50 5x10-10 M) [12]
compound 2 [PMID: 15546730] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.0 pIC50 4
⤷ pIC50 9.0 (IC50 1x10-9 M) [4]
compound 31 [PMID: 24915291] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.6 pIC50 10
⤷ pIC50 8.6 (IC50 2.7x10-9 M) [10]
compound 38 [PMID: 24915291] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.4 pIC50 10
⤷ pIC50 8.4 (IC50 4.2x10-9 M) [10]
eCF506 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.3 pIC50 7
⤷ pIC50 8.3 (IC50 5.4x10-9 M) [7]
CEP-11981 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.1 pIC50 9
⤷ pIC50 8.1 (IC50 8x10-9 M) [9]
nemtabrutinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.0 pIC50 15
⤷ pIC50 8.0 (IC50 9.7x10-9 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 2
⤷ pIC50 7.2 (IC50 6.8x10-8 M) [2]
PRN694 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 6.9 pIC50 23
⤷ pIC50 6.9 (IC50 1.25x10-7 M) [23]
compound 25 [PMID: 31260299] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 6.8 pIC50 22
⤷ pIC50 6.8 (IC50 1.5x10-7 M) [22]
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 3
⤷ pIC50 <6.0 (IC50 >1x10-6 M) [3]
JNJ-64264681 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.5 pIC50 19
⤷ pIC50 5.5 (IC50 3.13x10-6 M) [19]
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: 6,20
Key to terms and symbols Click column headers to sort
Target used in screen: BLK
Ligand Sp. Type Action Value Parameter
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 9.7 pKd
PD-173955 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.8 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 8.3 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 8.0 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.8 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.6 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 7.5 pKd
canertinib Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 7.3 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.2 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: 1,8
Key to terms and symbols Click column headers to sort
Target used in screen: Blk/BLK
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
Lck inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.5 0.0 0.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.6 -0.5 0.5
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 3.0
PDGF RTK inhibitor Small molecule or natural product Hs Inhibitor Inhibition 8.6 0.0 0.0
Src kinase inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 9.9 0.0 0.0
GSK-3 inhibitor IX Small molecule or natural product Hs Inhibitor Inhibition 11.3 1.0 5.0
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 12.3
SU6656 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 13.9 10.0 2.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 15.8 1.0 0.0
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 20.7
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
BLK is a B cell-specific kinase. In Blk knockout mice B cells develop normally and show unaltered in vitro activation and humoral immune responses to T cell-dependent and -independent antigens, a result which is indicative of functional redundancy of Blk in B cell development and immune responses [18]. Genetic variants in BLK have been reported to associate with autoimmune conditions [25], including systemic lupus erythematosus (SLE) [5], primary Sjögren's syndrome [16-17], asthma and allergic rhinitis [11].
Cell Type Associations
Immuno Cell Type:  B cells
Cell Ontology Term:   B cell (CL:0000236)
Comment:  BLK is only expressed in B cells.
References:  13
Immuno Process Associations
Immuno Process:  Immune regulation
Immuno Process:  Cellular signalling
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Maturity-onset diabetes of the young, type 11; MODY11
Synonyms: Maturity-onset diabetes of the young [Orphanet: ORPHA552] [OMIM: 606391] [Disease Ontology: DOID:0050524]
MODY [Orphanet: ORPHA552] [OMIM: 606391]
Disease Ontology: DOID:0050524
OMIM: 613375, 606391
Orphanet: ORPHA552
Disease:  Systemic lupus erythematosus, susceptibility to, 12; SLEB12
Synonyms: Systemic lupus erythematosus [Orphanet: ORPHA536] [Disease Ontology: DOID:9074]
Disease Ontology: DOID:9074
OMIM: 612254
Orphanet: ORPHA536

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. 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]

3. 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]

4. 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]

5. Chen Y, Wu Q, Shao Y, Zhang J, Guan M, Wan J, Yu B, Zhang W. (2012) Identify the association between polymorphisms of BLK and systemic lupus erythematosus through unlabelled probe-based high-resolution melting analysis. Int J Immunogenet, 39 (4): 321-7. [PMID:22313735]

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. 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]

8. 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]

9. Hudkins RL, Becknell NC, Zulli AL, Underiner TL, Angeles TS, Aimone LD, Albom MS, Chang H, Miknyoczki SJ, Hunter K et al.. (2012) Synthesis and biological profile of the pan-vascular endothelial growth factor receptor/tyrosine kinase with immunoglobulin and epidermal growth factor-like homology domains 2 (VEGF-R/TIE-2) inhibitor 11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (CEP-11981): a novel oncology therapeutic agent. J Med Chem, 55 (2): 903-13. [PMID:22148921]

10. 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]

11. Liu Y, Ke X, Kang HY, Wang XQ, Shen Y, Hong SL. (2016) Genetic risk of TNFSF4 and FAM167A-BLK polymorphisms in children with asthma and allergic rhinitis in a Han Chinese population. J Asthma, 53 (6): 567-75. [PMID:27088737]

12. Lou Y, Owens TD, Kuglstatter A, Kondru RK, Goldstein DM. (2012) Bruton's tyrosine kinase inhibitors: approaches to potent and selective inhibition, preclinical and clinical evaluation for inflammatory diseases and B cell malignancies. J Med Chem, 55 (10): 4539-50. [PMID:22394077]

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

14. Metzler WJ, Leiting B, Pryor K, Mueller L, Farmer BT. (1996) The three-dimensional solution structure of the SH2 domain from p55blk kinase. Biochemistry, 35 (20): 6201-11. [PMID:8639560]

15. Reiff SD, Mantel R, Smith LL, Greene JT, Muhowski EM, Fabian CA, Goettl VM, Tran M, Harrington BK, Rogers KA et al.. (2018) The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation. Cancer Discov, 8 (10): 1300-1315. [PMID:30093506]

16. Sun F, Li P, Chen H, Wu Z, Xu J, Shen M, Leng X, Shi Q, Zhang W, Tian X et al.. (2013) Association studies of TNFSF4, TNFAIP3 and FAM167A-BLK polymorphisms with primary Sjogren's syndrome in Han Chinese. J Hum Genet, 58 (7): 475-9. [PMID:23635951]

17. Sun F, Xu J, Wu Z, Li P, Chen H, Su J, You X, Li M, Zhao Y, Tian X et al.. (2013) Polymorphisms in the FAM167A-BLK, but not BANK1, are associated with primary Sjögren's syndrome in a Han Chinese population. Clin Exp Rheumatol, 31 (5): 704-10. [PMID:23899688]

18. Texido G, Su IH, Mecklenbräuker I, Saijo K, Malek SN, Desiderio S, Rajewsky K, Tarakhovsky A. (2000) The B-cell-specific Src-family kinase Blk is dispensable for B-cell development and activation. Mol Cell Biol, 20 (4): 1227-33. [PMID:10648608]

19. Tichenor MS, Wiener JJM, Rao NL, Bacani GM, Wei J, Pooley Deckhut C, Barbay JK, Kreutter KD, Chang L, Clancy KW et al.. (2022) Discovery of JNJ-64264681: A Potent and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase. J Med Chem, 65 (21): 14326-14336. [PMID:36314537]

20. 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]

21. Yang J, Shibu MA, Kong L, Luo J, BadrealamKhan F, Huang Y, Tu ZC, Yun CH, Huang CY, Ding K et al.. (2020) Design, Synthesis, and Structure-Activity Relationships of 1,2,3-Triazole Benzenesulfonamides as New Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) Inhibitors. J Med Chem, 63 (5): 2114-2130. [PMID:31244114]

22. Yao X, Sun X, Jin S, Yang L, Xu H, Rao Y. (2019) Discovery of 4-Aminoquinoline-3-carboxamide Derivatives as Potent Reversible Bruton's Tyrosine Kinase Inhibitors for the Treatment of Rheumatoid Arthritis. J Med Chem, 62 (14): 6561-6574. [PMID:31260299]

23. Zhong Y, Dong S, Strattan E, Ren L, Butchar JP, Thornton K, Mishra A, Porcu P, Bradshaw JM, Bisconte A et al.. (2015) Targeting interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) using a novel covalent inhibitor PRN694. J Biol Chem, 290 (10): 5960-78. [PMID:25593320]

24. 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]

25. Zhou Y, Li X, Wang G, Li X. (2016) Association of FAM167A-BLK rs2736340 Polymorphism with Susceptibility to Autoimmune Diseases: A Meta-Analysis. Immunol Invest, 45 (4): 336-48. [PMID:27105348]

How to cite this page

Src family: BLK proto-oncogene, Src family tyrosine kinase. Last modified on 02/11/2022. Accessed on 13/10/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1940.