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 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

   GtoImmuPdb view: ON :     LCK proto-oncogene, Src family tyrosine kinase has curated data in GtoImmuPdb

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
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:  14
Image of receptor 3D structure from RCSB PDB
Description:  FREE P56LCK SH2 DOMAIN
PDB Id:  1BHH
Resolution:  1.9Å
Species:  Human
References:  31
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 Units Reference
acalabrutinib Hs Inhibition <6.0 pEC50 4
pEC50 <6.0 (EC50 >1x10-6 M) [4]
eCF506 Hs Inhibition >9.3 pIC50 10
pIC50 >9.3 (IC50 <5x10-10 M) [10]
Lck inhibitor Hs Inhibition >9.0 pIC50 5
pIC50 >9.0 (IC50 <1x10-9 M) [5]
compound 2 [PMID: 15546730] Hs Inhibition 9.0 pIC50 7
pIC50 9.0 (IC50 1x10-9 M) [7]
WH-4-023 Hs Inhibition 8.7 pIC50 24
pIC50 8.7 (IC50 2x10-9 M) [24]
CCT241161 Hs Inhibition 8.5 pIC50 12
pIC50 8.5 (IC50 3x10-9 M) [12]
saracatinib Hs Inhibition >8.4 pIC50 16
pIC50 >8.4 (IC50 <4x10-9 M) [16]
PP2 Hs Inhibition 8.4 pIC50 15
pIC50 8.4 (IC50 4x10-9 M) [15]
compound 30 [PMID: 17280833] Hs Inhibition 8.3 pIC50 9
pIC50 8.3 (IC50 5x10-9 M) [9]
PP1 Hs Inhibition 8.3 pIC50 15
pIC50 8.3 (IC50 5x10-9 M) [15]
ibrutinib Hs Inhibition 8.2 pIC50 6
pIC50 8.2 (IC50 6.3x10-9 M) [6]
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 22
pIC50 7.8 (IC50 1.6x10-8 M) [22]
Description: Assayed using AMPK heterotrimeric complex containing α2, β1, γ1 subunits
CCT196969 Hs Inhibition 7.7 pIC50 12
pIC50 7.7 (IC50 2x10-8 M) [12]
compound 7 [PMID: 22464456] Hs Inhibition 7.4 pIC50 25
pIC50 7.4 (IC50 3.92x10-8 M) [25]
7-hydroxystaurosporine Hs Inhibition 7.3 pIC50 17
pIC50 7.3 (IC50 5x10-8 M) [17]
JNJ-28312141 Hs Inhibition 7.1 pIC50 23
pIC50 7.1 (IC50 8.8x10-8 M) [23]
SU6656 Hs Inhibition 6.8 pIC50 2
pIC50 6.8 (IC50 1.5x10-7 M) [2]
theliatinib Hs Inhibition 6.8 pIC50 27
pIC50 6.8 (IC50 1.76x10-7 M) [27]
compound 19a [PMID: 21855335] Hs Inhibition 6.7 pIC50 33
pIC50 6.7 (IC50 1.8x10-7 M) [33]
compound 36 [PMID: 21958547] Hs Inhibition 6.1 pIC50 18
pIC50 6.1 (IC50 7.72x10-7 M) [18]
pexidartinib Hs Inhibition 6.1 pIC50 30
pIC50 6.1 (IC50 8.6x10-7 M) [30]
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: 8,32

Key to terms and symbols Click column headers to sort
Target used in screen: LCK
Ligand Sp. Type Action Affinity Units
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: 1,11

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 »
Physiological Functions Comments
Lck is required for the T cell receptor (TCR)-mediated signalling underlying normal T cell development and activation [13,19,28-29]. 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. 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]

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. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. Gommermann N, Buehlmayer P, von Matt A, Breitenstein W, Masuya K, Pirard B, Furet P, Cowan-Jacob SW, Weckbecker G. (2010) New pyrazolo[1,5a]pyrimidines as orally active inhibitors of Lck. Bioorg. Med. Chem. Lett., 20 (12): 3628-31. [PMID:20483608]

15. Hanke JH, Gardner JP, Dow RL, Changelian PS, Brissette WH, Weringer EJ, Pollok BA, Connelly PA. (1996) Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. J. Biol. Chem., 271 (2): 695-701. [PMID:8557675]

16. 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]

17. 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]

18. 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]

19. 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]

20. 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]

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

22. Machrouhi F, Ouhamou N, Laderoute K, Calaoagan J, Bukhtiyarova M, Ehrlich PJ, Klon AE. (2010) The rational design of a novel potent analogue of the 5'-AMP-activated protein kinase inhibitor compound C with improved selectivity and cellular activity. Bioorg. Med. Chem. Lett., 20 (22): 6394-9. [PMID:20932747]

23. Manthey CL, Johnson DL, Illig CR, Tuman RW, Zhou Z, Baker JF, Chaikin MA, Donatelli RR, Franks CF, Zeng L et al.. (2009) JNJ-28312141, a novel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia. Mol. Cancer Ther., 8 (11): 3151-61. [PMID:19887542]

24. Martin MW, Newcomb J, Nunes JJ, McGowan DC, Armistead DM, Boucher C, Buchanan JL, Buckner W, Chai L, Elbaum D et al.. (2006) Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity. J. Med. Chem., 49 (16): 4981-91. [PMID:16884310]

25. McLean LR, Zhang Y, Zaidi N, Bi X, Wang R, Dharanipragada R, Jurcak JG, Gillespy TA, Zhao Z, Musick KY et al.. (2012) X-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2-inducible tyrosine kinase. Bioorg. Med. Chem. Lett., 22 (9): 3296-300. [PMID:22464456]

26. Palacios EH, Weiss A. (2004) Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation. Oncogene, 23 (48): 7990-8000. [PMID:15489916]

27. 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]

28. Seddon B, Zamoyska R. (2002) TCR signals mediated by Src family kinases are essential for the survival of naive T cells. J. Immunol., 169 (6): 2997-3005. [PMID:12218114]

29. Straus DB, Weiss A. (1992) Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor. Cell, 70 (4): 585-93. [PMID:1505025]

30. Tap WD, Wainberg ZA, Anthony SP, Ibrahim PN, Zhang C, Healey JH, Chmielowski B, Staddon AP, Cohn AL, Shapiro GI et al.. (2015) Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor. N. Engl. J. Med., 373 (5): 428-37. [PMID:26222558]

31. Tong L, Warren TC, Lukas S, Schembri-King J, Betageri R, Proudfoot JR, Jakes S. (1998) Carboxymethyl-phenylalanine as a replacement for phosphotyrosine in SH2 domain binding. J. Biol. Chem., 273 (32): 20238-42. [PMID:9685372]

32. 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]

33. Zeng H, Belanger DB, Curran PJ, Shipps Jr GW, Miao H, Bracken JB, Arshad Siddiqui M, Malkowski M, Wang Y. (2011) Discovery of novel imidazo[1,2-a]pyrazin-8-amines as Brk/PTK6 inhibitors. Bioorg. Med. Chem. Lett., 21 (19): 5870-5. [PMID:21855335]

How to cite this page

Src family: LCK proto-oncogene, Src family tyrosine kinase. Last modified on 26/04/2018. Accessed on 16/01/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2053.