BLK proto-oncogene, Src family tyrosine kinase | Src family | IUPHAR Guide to IMMUNOPHARMACOLOGY

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BLK proto-oncogene, Src family tyrosine kinase

  Target has curated data in GtoImmuPdb

Target id: 1940

Nomenclature: BLK proto-oncogene, Src family tyrosine kinase

Abbreviated Name: Blk

Family: Src 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 - 505 8p23-p22 BLK BLK proto-oncogene, Src family tyrosine kinase
Mouse - 499 14 D1 Blk B lymphoid kinase
Rat - 499 15p12 Blk BLK proto-oncogene
Previous and Unofficial Names
B lymphocyte kinase | p55-Blk | BLK proto-oncogene
Database Links
BRENDA
CATH/Gene3D
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:  NMR ensemble of BLK SH3 domain
PDB Id:  1BLJ
Resolution:  0.0Å
Species:  Mouse
References:  14
Enzyme Reaction
EC Number: 2.7.10.2

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 Affinity Parameter Reference
WZ4002 Hs Inhibition 6.7 pKd 20
pKd 6.7 (Kd 2x10-7 M) [20]
ibrutinib 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] Hs Inhibition 9.0 pIC50 4
pIC50 9.0 (IC50 1x10-9 M) [4]
compound 31 [PMID: 24915291] Hs Inhibition 8.6 pIC50 10
pIC50 8.6 (IC50 2.7x10-9 M) [10]
compound 38 [PMID: 24915291] Hs Inhibition 8.4 pIC50 10
pIC50 8.4 (IC50 4.2x10-9 M) [10]
eCF506 Hs Inhibition 8.3 pIC50 7
pIC50 8.3 (IC50 5.4x10-9 M) [7]
CEP-11981 Hs Inhibition 8.1 pIC50 9
pIC50 8.1 (IC50 8x10-9 M) [9]
compound 9 [PMID: 26006010] Hs Inhibition 7.2 pIC50 2
pIC50 7.2 (IC50 6.8x10-8 M) [2]
PRN694 Hs Inhibition 6.9 pIC50 19
pIC50 6.9 (IC50 1.25x10-7 M) [19]
acalabrutinib Hs Inhibition <6.0 pIC50 3
pIC50 <6.0 (IC50 >1x10-6 M) [3]
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: 6,18

Key to terms and symbols Click column headers to sort
Target used in screen: BLK
Ligand Sp. Type Action Affinity Parameter
dasatinib Hs Inhibitor Inhibition 9.7 pKd
PD-173955 Hs Inhibitor Inhibition 8.8 pKd
bosutinib Hs Inhibitor Inhibition 8.5 pKd
foretinib Hs Inhibitor Inhibition 8.3 pKd
JNJ-28312141 Hs Inhibitor Inhibition 8.0 pKd
staurosporine Hs Inhibitor Inhibition 7.8 pKd
tamatinib Hs Inhibitor Inhibition 7.6 pKd
AST-487 Hs Inhibitor Inhibition 7.5 pKd
canertinib Hs Inhibitor Inhibition 7.3 pKd
sunitinib 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
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 Hs Inhibitor Inhibition 1.5 0.0 0.0
staurosporine Hs Inhibitor Inhibition 1.6 -0.5 0.5
dasatinib Hs Inhibitor Inhibition 3.0
PDGF RTK inhibitor Hs Inhibitor Inhibition 8.6 0.0 0.0
Src kinase inhibitor I Hs Inhibitor Inhibition 9.9 0.0 0.0
GSK-3 inhibitor IX Hs Inhibitor Inhibition 11.3 1.0 5.0
dovitinib Hs Inhibitor Inhibition 12.3
SU6656 Hs Inhibitor Inhibition 13.9 10.0 2.0
SU11652 Hs Inhibitor Inhibition 15.8 1.0 0.0
bosutinib 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 [17]. Genetic variants in BLK have been reported to associate with autoimmune conditions [21], including systemic lupus erythematosus (SLE) [5], primary Sjögren's syndrome [15-16], 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:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:0045087 innate immune response IBA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 2 GO processes
GO:0050853 B cell receptor signaling pathway IDA
GO:0050855 regulation of B cell receptor signaling pathway TAS
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 2 GO processes
GO:0050853 B cell receptor signaling pathway IDA
GO:0050855 regulation of B cell receptor signaling pathway TAS
Clinically-Relevant Mutations and Pathophysiology
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. 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]

16. 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]

17. 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]

18. 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]

19. 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]

20. 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]

21. 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 16/01/2018. Accessed on 18/02/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1940.