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

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LCK proto-oncogene, Src family tyrosine kinase

  Target has curated data in GtoImmuPdb

Target id: 2053

Nomenclature: LCK proto-oncogene, Src family tyrosine kinase

Abbreviated Name: Lck

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 - 509 1p34.3 LCK LCK proto-oncogene, Src family tyrosine kinase
Mouse - 520 4 D2.2 Lck lymphocyte protein tyrosine kinase
Rat - 509 5 q36 Lck LCK proto-oncogene, Src family tyrosine kinase
Previous and Unofficial Names
Hck-3 | Leukocyte C-terminal Src kinase | p56-LCK | Protein YT16 | lymphocyte-specific protein tyrosine kinase | LCK proto-oncogene
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
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  LCK complexed with a pyrazolopyrimidine
PDB Id:  3MPM
Resolution:  1.95Å
Species:  Human
References:  16
Image of receptor 3D structure from RCSB PDB
Description:  FREE P56LCK SH2 DOMAIN
PDB Id:  1BHH
Resolution:  1.9Å
Species:  Human
References:  34
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 Value Parameter Reference
belizatinib Hs Inhibition 7.6 pKd 22
pKd 7.6 (Kd 2.8x10-8 M) [22]
Description: Binding affinity in vitro.
ZAK inhibitor 6p Hs Inhibition 6.8 pKd 37
pKd 6.8 (Kd 1.6x10-7 M) [37]
DDR1/2 inhibitor 5n Hs Inhibition 6.7 pKd 35
pKd 6.7 (Kd 1.8x10-7 M) [35]
neolymphostin A Hs Inhibition 5.3 pKd 8
pKd 5.3 (Kd 4.6x10-6 M) [8]
acalabrutinib Hs Inhibition <6.0 pEC50 4
pEC50 <6.0 (EC50 >1x10-6 M) [4]
eCF506 Hs Inhibition >9.3 pIC50 12
pIC50 >9.3 (IC50 <5x10-10 M) [12]
Lck inhibitor Hs Inhibition >9.0 pIC50 6
pIC50 >9.0 (IC50 <1x10-9 M) [6]
compound 2 [PMID: 15546730] Hs Inhibition 9.0 pIC50 9
pIC50 9.0 (IC50 1x10-9 M) [9]
WH-4-023 Hs Inhibition 8.7 pIC50 27
pIC50 8.7 (IC50 2x10-9 M) [27]
CCT241161 Hs Inhibition 8.5 pIC50 14
pIC50 8.5 (IC50 3x10-9 M) [14]
saracatinib Hs Inhibition >8.4 pIC50 18
pIC50 >8.4 (IC50 <4x10-9 M) [18]
PP2 Hs Inhibition 8.4 pIC50 17
pIC50 8.4 (IC50 4x10-9 M) [17]
compound 30 [PMID: 17280833] Hs Inhibition 8.3 pIC50 11
pIC50 8.3 (IC50 5x10-9 M) [11]
PP1 Hs Inhibition 8.3 pIC50 17
pIC50 8.3 (IC50 5x10-9 M) [17]
ibrutinib Hs Inhibition 8.2 pIC50 7
pIC50 8.2 (IC50 6.3x10-9 M) [7]
compound 23 [PMID: 17600705] Hs Inhibition 8.1 pIC50 3
pIC50 8.1 (IC50 8.5x10-9 M) [3]
dorsomorphin Hs Inhibition 7.8 pIC50 25
pIC50 7.8 (IC50 1.6x10-8 M) [25]
Description: Assayed using AMPK heterotrimeric complex containing α2, β1, γ1 subunits
CCT196969 Hs Inhibition 7.7 pIC50 14
pIC50 7.7 (IC50 2x10-8 M) [14]
compound 7 [PMID: 22464456] Hs Inhibition 7.4 pIC50 28
pIC50 7.4 (IC50 3.92x10-8 M) [28]
7-hydroxystaurosporine Hs Inhibition 7.3 pIC50 19
pIC50 7.3 (IC50 5x10-8 M) [19]
JNJ-28312141 Hs Inhibition 7.1 pIC50 26
pIC50 7.1 (IC50 8.8x10-8 M) [26]
SU6656 Hs Inhibition 6.8 pIC50 2
pIC50 6.8 (IC50 1.5x10-7 M) [2]
HMPL-309 Hs Inhibition 6.8 pIC50 30
pIC50 6.8 (IC50 1.76x10-7 M) [30]
compound 19a [PMID: 21855335] Hs Inhibition 6.7 pIC50 38
pIC50 6.7 (IC50 1.8x10-7 M) [38]
compound 36 [PMID: 21958547] Hs Inhibition 6.1 pIC50 20
pIC50 6.1 (IC50 7.72x10-7 M) [20]
pexidartinib Hs Inhibition 6.1 pIC50 33
pIC50 6.1 (IC50 8.6x10-7 M) [33]
GSK2646264 Hs Inhibition 5.4 pIC50 5
pIC50 5.4 (IC50 3.981x10-6 M) [5]
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: 10,36

Key to terms and symbols Click column headers to sort
Target used in screen: LCK
Ligand Sp. Type Action Value Parameter
dasatinib Hs Inhibitor Inhibition 9.7 pKd
bosutinib Hs Inhibitor Inhibition 9.2 pKd
PD-173955 Hs Inhibitor Inhibition 9.0 pKd
foretinib Hs Inhibitor Inhibition 8.2 pKd
AST-487 Hs Inhibitor Inhibition 8.0 pKd
vandetanib Hs Inhibitor Inhibition 7.8 pKd
staurosporine Hs Inhibitor Inhibition 7.5 pKd
tamatinib Hs Inhibitor Inhibition 7.5 pKd
crizotinib Hs Inhibitor Inhibition 7.5 pKd
masitinib Hs Inhibitor Inhibition 7.5 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: 1,13

Key to terms and symbols Click column headers to sort
Target used in screen: Lck activated
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
Lck inhibitor Hs Inhibitor Inhibition -3.0 2.0
tivozanib Hs Inhibitor Inhibition -2.0 1.0
Src kinase inhibitor I Hs Inhibitor Inhibition -2.0 0.0
staurosporine Hs Inhibitor Inhibition -1.5 0.0
PDGF RTK inhibitor Hs Inhibitor Inhibition 0.0 0.0
GSK-3 inhibitor IX Hs Inhibitor Inhibition 1.0 19.0
TWS119 Hs Inhibitor Inhibition 4.0 0.0
midostaurin Hs Inhibitor Inhibition 5.0 6.0
indirubin derivative E804 Hs Inhibitor Inhibition 5.0 8.0
K-252a Hs Inhibitor Inhibition 6.0 8.0
Target used in screen: Lck/LCK
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
dasatinib Hs Inhibitor Inhibition 0.3
Lck inhibitor Hs Inhibitor Inhibition 1.1 1.0 -1.0
PDGF RTK inhibitor Hs Inhibitor Inhibition 1.6 1.0 -1.0
staurosporine Hs Inhibitor Inhibition 1.8 -0.5 4.5
bosutinib Hs Inhibitor Inhibition 1.9
vandetanib Hs Inhibitor Inhibition 3.6
Src kinase inhibitor I Hs Inhibitor Inhibition 4.7 0.0 -1.0
dovitinib Hs Inhibitor Inhibition 4.7
masitinib Hs Inhibitor Inhibition 7.6
SU11652 Hs Inhibitor Inhibition 11.8 12.0 2.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
Phosphorylation and activation of Lck is an early and critical step in pre-TCR (T cell receptor) and TCR signalling. Activated Lck phosphorylates immunoreceptor tyrosine-based activation motifs of the ζ chain of the TCR leading to recruitment and activation of ZAP-70 tyrosine kinase, and activation of downstream MAPKs and NF-κB. TCR-based signals are required at several stages of T-cell development and it is thought that Lck is the major contributor to TCR signal transduction (with the related Src tyrosine kinase Fyn also playing a role) [29]. JNK pathway-associated phosphatase (JKAP or JSP-1) is reported to dephosphorylate Lck and attenuate TCR signalling [23], with the likelihood that this mechanism would suppressT-cell-mediated immunity and autoimmunity.
Cell Type Associations
Immuno Cell Type:  T cells
References:  24
Immuno Cell Type:  Natural killer cells
Cell Ontology Term:   natural killer cell (CL:0000623)
References:  24
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:0050900 leukocyte migration TAS
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 3 GO processes
GO:0030217 T cell differentiation IMP
GO:0031295 T cell costimulation TAS
GO:0050870 positive regulation of T cell activation IDA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 6 GO processes
GO:0031295 T cell costimulation TAS
GO:0050852 T cell receptor signaling pathway TAS
GO:0050853 B cell receptor signaling pathway IBA
GO:0050862 positive regulation of T cell receptor signaling pathway NAS
GO:0050870 positive regulation of T cell activation IDA
GO:0051249 regulation of lymphocyte activation NAS
Immuno Process:  Immune system development
GO Annotations:  Associated to 2 GO processes
GO:0030097 hemopoiesis NAS
GO:0030217 T cell differentiation IMP
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 4 GO processes
GO:0031295 T cell costimulation TAS
GO:0050870 positive regulation of T cell activation IDA
GO:0050900 leukocyte migration TAS
GO:1903039 positive regulation of leukocyte cell-cell adhesion IMP
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 7 GO processes
GO:0030217 T cell differentiation IMP
GO:0031295 T cell costimulation TAS
GO:0050852 T cell receptor signaling pathway TAS
GO:0050853 B cell receptor signaling pathway IBA
GO:0050862 positive regulation of T cell receptor signaling pathway NAS
GO:0050870 positive regulation of T cell activation IDA
GO:0051249 regulation of lymphocyte activation NAS
Physiological Functions Comments
Lck is required for the T cell receptor (TCR)-mediated signalling underlying normal T cell development and activation [15,21,31-32]. Selective inhibition of Lck offers a new strategy for the treatment of graft rejection and/or T cell-mediated autoimmune and inflammatory disease (eg rheumatoid arthritis, psoriasis, multiple sclerosis, atherosclerosis).
Clinically-Relevant Mutations and Pathophysiology
Disease:  Severe combined immunodeficiency due to LCK deficiency
Synonyms: Immunodeficiency 22; IMD22 [OMIM: 615758]
OMIM: 615758
Orphanet: ORPHA280142

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. Bain J, Plater L, Elliott M, Shpiro N, Hastie CJ, McLauchlan H, Klevernic I, Arthur JS, Alessi DR, Cohen P. (2007) The selectivity of protein kinase inhibitors: a further update. Biochem. J., 408 (3): 297-315. [PMID:17850214]

3. Bamborough P, Angell RM, Bhamra I, Brown D, Bull J, Christopher JA, Cooper AW, Fazal LH, Giordano I, Hind L et al.. (2007) N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck: indazoles as phenol isosteres with improved pharmacokinetics. Bioorg. Med. Chem. Lett., 17 (15): 4363-8. [PMID:17600705]

4. Barf TA, Jans CGJM, Man PADeA, Oubrie AA, Raaijmakers HCA, Rewinkel JBM, Sterrenburg J-G, Wijkmans JCHM. (2014) 4-imidazopyridazin-1-yl-benzamides and 4-imidazotriazin-1-yl-benzamides as btk inhibitors. Patent number: US20140155385 A1. Assignee: Barf TA, Jans CGJM, Man PADeA, Oubrie AA, Raaijmakers HCA, Rewinkel JBM, Sterrenburg J-G, Wijkmans JCHM. Priority date: 19/07/2011. Publication date: 05/06/2014.

5. Barker MD, Liddle J, Atkinson FL, Wilson DM, Dickson MC, Ramirez-Molina C, Lewis H, Davis RP, Somers DO, Neu M et al.. (2018) Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease. Bioorg. Med. Chem. Lett., 28 (21): 3458-3462. [PMID:30249354]

6. Burchat AF, Calderwood DJ, Hirst GC, Holman NJ, Johnston DN, Munschauer R, Rafferty P, Tometzki GB. (2000) Pyrrolo[2,3-d]pyrimidines containing an extended 5-substituent as potent and selective inhibitors of lck II. Bioorg. Med. Chem. Lett., 10 (19): 2171-4. [PMID:11012022]

7. 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]

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10. 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]

11. DiMauro EF, Newcomb J, Nunes JJ, Bemis JE, Boucher C, Buchanan JL, Buckner WH, Cheng A, Faust T, Hsieh F et al.. (2007) Discovery of 4-amino-5,6-biaryl-furo[2,3-d]pyrimidines as inhibitors of Lck: development of an expedient and divergent synthetic route and preliminary SAR. Bioorg. Med. Chem. Lett., 17 (8): 2305-9. [PMID:17280833]

12. 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]

13. 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]

14. Girotti MR, Lopes F, Preece N, Niculescu-Duvaz D, Zambon A, Davies L, Whittaker S, Saturno G, Viros A, Pedersen M et al.. (2015) Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma. Cancer Cell, 27 (1): 85-96. [PMID:25500121]

15. Goldman FD, Ballas ZK, Schutte BC, Kemp J, Hollenback C, Noraz N, Taylor N. (1998) Defective expression of p56lck in an infant with severe combined immunodeficiency. J. Clin. Invest., 102 (2): 421-9. [PMID:9664084]

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18. Hennequin LF, Allen J, Breed J, Curwen J, Fennell M, Green TP, Lambert-van der Brempt C, Morgentin R, Norman RA, Olivier A et al.. (2006) N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. J. Med. Chem., 49 (22): 6465-88. [PMID:17064066]

19. Jiang X, Zhao B, Britton R, Lim LY, Leong D, Sanghera JS, Zhou BB, Piers E, Andersen RJ, Roberge M. (2004) Inhibition of Chk1 by the G2 DNA damage checkpoint inhibitor isogranulatimide. Mol. Cancer Ther., 3 (10): 1221-7. [PMID:15486189]

20. Kim KH, Maderna A, Schnute ME, Hegen M, Mohan S, Miyashiro J, Lin L, Li E, Keegan S, Lussier J et al.. (2011) Imidazo[1,5-a]quinoxalines as irreversible BTK inhibitors for the treatment of rheumatoid arthritis. Bioorg. Med. Chem. Lett., 21 (21): 6258-63. [PMID:21958547]

21. Levin SD, Anderson SJ, Forbush KA, Perlmutter RM. (1993) A dominant-negative transgene defines a role for p56lck in thymopoiesis. EMBO J., 12 (4): 1671-80. [PMID:8385609]

22. Lewis RT, Bode CM, Choquette DM, Potashman M, Romero K, Stellwagen JC, Teffera Y, Moore E, Whittington DA, Chen H et al.. (2012) The discovery and optimization of a novel class of potent, selective, and orally bioavailable anaplastic lymphoma kinase (ALK) inhibitors with potential utility for the treatment of cancer. J. Med. Chem., 55 (14): 6523-40. [PMID:22734674]

23. Li JP, Yang CY, Chuang HC, Lan JL, Chen DY, Chen YM, Wang X, Chen AJ, Belmont JW, Tan TH. (2014) The phosphatase JKAP/DUSP22 inhibits T-cell receptor signalling and autoimmunity by inactivating Lck. Nat Commun, 5: 3618. [PMID:24714587]

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

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37. Yang J, Shibu MA, Kong L, Luo J, BadrealamKhan F, Huang Y, Tu ZC, Yun CH, Huang CY, Ding K et al.. (2019) 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., [Epub ahead of print]. DOI: 10.1021/acs.jmedchem.9b00664 [PMID:31244114]

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How to cite this page

Src family: LCK proto-oncogene, Src family tyrosine kinase. Last modified on 04/09/2019. Accessed on 21/10/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2053.