Target General Infomation
Target ID
T12499
Former ID
TTDS00407
Target Name
Lck tyrosine kinase
Gene Name
LCK
Synonyms
FYN; Protooncogene Syn; SLK; p59-Fyn; Proto-oncogene tyrosine-protein kinase LCK; LCK
Target Type
Successful
Disease Autoimmune diabetes [ICD10: E08-E13]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Chronic myelogenous leukaemia [ICD9: 205.1; ICD10: C92.1]
Multiple myeloma [ICD9: 203; ICD10: C90]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Function
Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T- cells in the thymus and in the function of mature T-cells. Plays a key role in T-cell antigen receptor (TCR)-linked signal transduction pathways. Constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors. Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, thereby recruiting the associated LCK protein to the vicinity of the TCR/CD3 complex. LCK then phosphorylates tyrosines residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the cytoplasmic tails of the TCR-gamma chains and CD3 subunits, initiating the TCR/CD3 signaling pathway. Once stimulated, the TCR recruits the tyrosine kinase ZAP70, that becomes phosphorylated and activated by LCK. Following this, a large number of signaling molecules are recruited, ultimately leading to lymphokine production. LCK also contributes tosignaling by other receptor molecules. Associates directly with the cytoplasmic tail of CD2, which leads to hyperphosphorylation and activation of LCK. Also plays a role in the IL2 receptor-linked signaling pathway that controls the T-cell proliferative response. Binding of IL2 to its receptor results in increased activity of LCK. Is expressed at all stages of thymocyte development and is required for the regulation of maturation events that are governed by both pre-TCR and mature alpha beta TCR. Phosphorylates other substrates including RUNX3, PTK2B/PYK2, the microtubule-associated protein MAPT, RHOH or TYROBP. {ECO:0000269|PubMed:16339550, ECO:0000269|PubMed:16709819, ECO:0000269|PubMed:20028775, ECO:0000269|PubMed:20100835, ECO:0000269|PubMed:20851766, ECO:0000269|PubMed:21269457, ECO:0000269|PubMed:22080863}.
BioChemical Class
Kinase
Target Validation
T12499
UniProt ID
EC Number
EC 2.7.10.2
Sequence
MGCGCSSHPEDDWMENIDVCENCHYPIVPLDGKGTLLIRNGSEVRDPLVTYEGSNPPASP
LQDNLVIALHSYEPSHDGDLGFEKGEQLRILEQSGEWWKAQSLTTGQEGFIPFNFVAKAN
SLEPEPWFFKNLSRKDAERQLLAPGNTHGSFLIRESESTAGSFSLSVRDFDQNQGEVVKH
YKIRNLDNGGFYISPRITFPGLHELVRHYTNASDGLCTRLSRPCQTQKPQKPWWEDEWEV
PRETLKLVERLGAGQFGEVWMGYYNGHTKVAVKSLKQGSMSPDAFLAEANLMKQLQHQRL
VRLYAVVTQEPIYIITEYMENGSLVDFLKTPSGIKLTINKLLDMAAQIAEGMAFIEERNY
IHRDLRAANILVSDTLSCKIADFGLARLIEDNEYTAREGAKFPIKWTAPEAINYGTFTIK
SDVWSFGILLTEIVTHGRIPYPGMTNPEVIQNLERGYRMVRPDNCPEELYQLMRLCWKER
PEDRPTFDYLRSVLEDFFTATEGQYQPQP
Structure
1BHF; 1BHH; 1CWD; 1CWE; 1FBZ; 1H92; 1IJR; 1KIK; 1LCJ; 1LCK; 1LKK; 1LKL; 1Q68; 1Q69; 1QPC; 1QPD; 1QPE; 1QPJ; 1X27; 2IIM; 2OF2; 2OF4; 2OFU; 2OFV; 2OG8; 2PL0; 2ZM1; 2ZM4; 2ZYB; 3AC1; 3AC2; 3AC3; 3AC4; 3AC5; 3AC8; 3ACJ; 3ACK; 3AD4; 3AD5; 3AD6; 3B2W; 3BRH; 3BYM; 3BYO; 3BYS;3BYU; 3KMM; 3KXZ; 3LCK; 3MPM; 4C3F; 4D8K; 1BHF; 1BHH; 1CWD; 1CWE; 1FBZ; 1H92; 1IJR; 1KIK; 1LCJ; 1LCK; 1LKK; 1LKL; 1Q68; 1Q69; 1QPC; 1QPD; 1QPE; 1QPJ; 1X27; 2IIM; 2OF2; 2OF4; 2OFU; 2OFV; 2OG8; 2PL0; 2ZM1; 2ZM4; 2ZYB; 3AC1; 3AC2; 3AC3; 3AC4; 3AC5; 3AC8; 3ACJ; 3ACK; 3AD4; 3AD5; 3AD6; 3B2W; 3BRH; 3BYM; 3BYO; 3BYS; 3BYU; 3KMM; 3KXZ; 3LCK; 3MPM; 4C3F; 4D8K
Drugs and Mode of Action
Drug(s) Dasatinib Drug Info Approved Chronic myelogenous leukaemia [528715], [536577], [541021], [551871]
CI-1040 Drug Info Phase 2 Discovery agent [521505], [541019]
Dasatinib Drug Info Phase 2 Multiple myeloma [536957], [541021]
VX-680 Drug Info Phase 2 Solid tumours [526974], [541056]
JNJ-26483327 Drug Info Phase 1 Cancer [522319]
Inhibitor (4-Phenoxy-phenyl)-quinazolin-4-yl-amine Drug Info [525876]
2-(3,4,5-Trihydroxy-benzylidene)-malononitrile Drug Info [533795]
3-(4-(o-toluidino)pyrimidin-2-ylamino)benzamide Drug Info [528928]
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole Drug Info [527308]
4-(3-Chloro-phenoxy)-6,7-dimethoxy-quinazoline Drug Info [551337]
4-Phenylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine Drug Info [527421]
6-o-tolylquinazolin-2-amine Drug Info [528429]
A-420983 Drug Info [527057]
A-641359 Drug Info [527790]
A-770041 Drug Info [527790]
AG-1879 Drug Info [529039]
BISINDOLYLMALEIMIDE IX Drug Info [525872]
BMS-536924 Drug Info [527711]
CEP-5104 Drug Info [529647]
CGP-57380 Drug Info [529039]
CI-1040 Drug Info [525872]
compound 19a Drug Info [531604]
compound 2 Drug Info [527295]
compound 23 Drug Info [528928]
compound 30 Drug Info [528657]
compound 7 Drug Info [531860]
Dasatinib Drug Info [536331], [536474], [536797]
GF-109203 Drug Info [525872]
GW-788388 Drug Info [528108]
JNJ-10198409 Drug Info [527932]
JNJ-26483327 Drug Info [550422]
JNJ-28312141 Drug Info [530495]
KN-62 Drug Info [525872]
L-779450 Drug Info [527836]
LAVENDUSTIN A Drug Info [533899]
Lck inhibitor Drug Info [525877]
Lck tyrosine kinase inhibitors Drug Info [543547]
Lymphocyte-specific tyrosine kinase inhibitors Drug Info [543547]
NM-PP1 Drug Info [529039]
PD-0166326 Drug Info [525862]
PD-0173952 Drug Info [525862]
PD-0173955 Drug Info [525862]
PD-0173956 Drug Info [525862]
PD-0173958 Drug Info [525862]
PD-0179483 Drug Info [525862]
PD-0180970 Drug Info [525862]
Phosphoaminophosphonic Acid-Adenylate Ester Drug Info [551374]
RO-316233 Drug Info [525872]
RPR-108518A Drug Info [551337]
STAUROSPORINONE Drug Info [525872]
SU 6656 Drug Info [529039]
TG-100435 Drug Info [528527]
VX-680 Drug Info [536474], [537553]
WH-4-023 Drug Info [528352]
Y-c[D-Pen-(3,5-diI)Tyr-GSFC]KR-NH2 Drug Info [534651]
Y-c[D-Pen-(3-I)Tyr-GSFC]KR-NH2 Drug Info [534651]
ZM-336372 Drug Info [529039]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway NF-kappa B signaling pathway
Osteoclast differentiation
Natural killer cell mediated cytotoxicity
T cell receptor signaling pathway
HTLV-I infection
Primary immunodeficiency
NetPath Pathway TCR Signaling Pathway
IL2 Signaling Pathway
PANTHER Pathway Parkinson disease
T cell activation
Pathway Interaction Database Atypical NF-kappaB pathway
Glypican 1 network
TCR signaling in na&amp
#xef
ve CD4+ T cells
Signaling events mediated by PTP1B
IL12-mediated signaling events
Regulation of p38-alpha and p38-beta
TCR signaling in na&amp
ve CD8+ T cells
Thromboxane A2 receptor signaling
SHP2 signaling
IL2-mediated signaling events
CXCR4-mediated signaling events
Class I PI3K signaling events
IL2 signaling events mediated by PI3K
amb2 Integrin signaling
EPHA forward signaling
PDGFR-beta signaling pathway
IL2 signaling events mediated by STAT5
Ephrin B reverse signaling
Alpha-synuclein signaling
Reactome GPVI-mediated activation cascade
PIP3 activates AKT signaling
Regulation of KIT signaling
Phosphorylation of CD3 and TCR zeta chains
Translocation of ZAP-70 to Immunological synapse
Generation of second messenger molecules
PECAM1 interactions
Constitutive Signaling by Aberrant PI3K in Cancer
DAP12 signaling
CD28 co-stimulation
CD28 dependent PI3K/Akt signaling
CD28 dependent Vav1 pathway
CTLA4 inhibitory signaling
PD-1 signaling
Interleukin-2 signaling
WikiPathways Notch Signaling Pathway
Interferon type I signaling pathways
IL-2 Signaling Pathway
Inflammatory Response Pathway
Signaling by SCF-KIT
DAP12 interactions
Host Interactions of HIV factors
PIP3 activates AKT signaling
T-Cell Receptor and Co-stimulatory Signaling
B Cell Receptor Signaling Pathway
TSLP Signaling Pathway
TCR signaling
Costimulation by the CD28 family
References
Ref 521505ClinicalTrials.gov (NCT00033384) CI-1040 in Treating Patients With Advanced Breast, Colon, Pancreatic, or Non-Small Cell Lung Cancer. U.S. National Institutes of Health.
Ref 522319ClinicalTrials.gov (NCT00676299) A Safety and Dose-finding Study of JNJ-26483327, a Drug in Development for Cancer, for Patients With Advanced and/or Refractory Solid Malignancies.. U.S. National Institutes of Health.
Ref 526974Nat Med. 2004 Mar;10(3):262-7. Epub 2004 Feb 22.VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo.
Ref 5287152006 drug approvals: finding the niche. Nat Rev Drug Discov. 2007 Feb;6(2):99-101.
Ref 536577Dasatinib: a tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia. Clin Ther. 2007 Nov;29(11):2289-308.
Ref 536957Current and future treatments of bone metastases. Expert Opin Emerg Drugs. 2008 Dec;13(4):609-27.
Ref 541019(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5676).
Ref 541021(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5678).
Ref 541056(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5718).
Ref 551871Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
Ref 525862Biochem Pharmacol. 2000 Oct 1;60(7):885-98.Biochemical and cellular effects of c-Src kinase-selective pyrido[2, 3-d]pyrimidine tyrosine kinase inhibitors.
Ref 525872Biochem J. 2000 Oct 1;351(Pt 1):95-105.Specificity and mechanism of action of some commonly used protein kinase inhibitors.
Ref 525876Bioorg Med Chem Lett. 2000 Oct 2;10(19):2167-70.Pyrrolo[2,3-d]pyrimidines containing an extended 5-substituent as potent and selective inhibitors of lck I.
Ref 525877Pyrrolo[2,3-d]pyrimidines containing an extended 5-substituent as potent and selective inhibitors of lck II. Bioorg Med Chem Lett. 2000 Oct 2;10(19):2171-4.
Ref 527057Bioorg Med Chem Lett. 2004 May 17;14(10):2613-6.A-420983: a potent, orally active inhibitor of lck with efficacy in a model of transplant rejection.
Ref 527295Discovery of novel 2-(aminoheteroaryl)-thiazole-5-carboxamides as potent and orally active Src-family kinase p56(Lck) inhibitors. Bioorg Med Chem Lett. 2004 Dec 20;14(24):6061-6.
Ref 527308J Med Chem. 2004 Dec 2;47(25):6239-47.Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole.
Ref 527421J Med Chem. 2005 Feb 10;48(3):710-22.Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors.
Ref 527711J Med Chem. 2005 Sep 8;48(18):5639-43.Discovery of a (1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo antitumor activity.
Ref 527790Bioorg Med Chem Lett. 2006 Jan 1;16(1):118-22. Epub 2005 Oct 10.Discovery of A-770041, a src-family selective orally active lck inhibitor that prevents organ allograft rejection.
Ref 527836Bioorg Med Chem Lett. 2006 Jan 15;16(2):378-81. Epub 2005 Nov 2.The identification of potent and selective imidazole-based inhibitors of B-Raf kinase.
Ref 527932J Med Chem. 2005 Dec 29;48(26):8163-73.(6,7-Dimethoxy-2,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenylamines: platelet-derived growth factor receptor tyrosine kinase inhibitors with broad antiproliferative activity against tumor cells.
Ref 528108J Med Chem. 2006 Apr 6;49(7):2210-21.Discovery of 4-{4-[3-(pyridin-2-yl)-1H-pyrazol-4-yl]pyridin-2-yl}-N-(tetrahydro-2H- pyran-4-yl)benzamide (GW788388): a potent, selective, and orally active transforming growth factor-beta type I receptor inhibitor.
Ref 528352Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity. J Med Chem. 2006 Aug 10;49(16):4981-91.
Ref 528429J Med Chem. 2006 Sep 21;49(19):5671-86.Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: synthesis, SAR, and in vivo anti-inflammatory activity.
Ref 528527Bioorg Med Chem Lett. 2007 Feb 1;17(3):602-8. Epub 2006 Nov 7.Discovery of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine--a potent, orally active Src kinase inhibitor with anti-tumor activity in preclinical assays.
Ref 528657Discovery 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. 2007 Apr 15;17(8):2305-9. Epub 2007 Jan 25.
Ref 528928Bioorg Med Chem Lett. 2007 Aug 1;17(15):4363-8. Epub 2007 Apr 13.N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck: indazoles as phenol isosteres with improved pharmacokinetics.
Ref 529039Biochem J. 2007 Dec 15;408(3):297-315.The selectivity of protein kinase inhibitors: a further update.
Ref 529647J Med Chem. 2008 Sep 25;51(18):5680-9. Epub 2008 Aug 21.Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models.
Ref 530495JNJ-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. 2009 Nov;8(11):3151-61.
Ref 531604Discovery of novel imidazo[1,2-a]pyrazin-8-amines as Brk/PTK6 inhibitors. Bioorg Med Chem Lett. 2011 Oct 1;21(19):5870-5.
Ref 531860X-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2-inducible tyrosine kinase. Bioorg Med Chem Lett. 2012 May 1;22(9):3296-300.
Ref 533795J Med Chem. 1993 Nov 12;36(23):3556-64.Tyrphostins. 3. Structure-activity relationship studies of alpha-substituted benzylidenemalononitrile 5-S-aryltyrphostins.
Ref 533899J Med Chem. 1993 Oct 1;36(20):3010-4.Non-amine based analogues of lavendustin A as protein-tyrosine kinase inhibitors.
Ref 534651J Med Chem. 1998 Jun 18;41(13):2252-60.Discovery of a novel series of potent and selective substrate-based inhibitors of p60c-src protein tyrosine kinase: conformational and topographical constraintsin peptide design.
Ref 536331Multi-target therapeutics: when the whole is greater than the sum of the parts. Drug Discov Today. 2007 Jan;12(1-2):34-42. Epub 2006 Nov 28.
Ref 536474A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
Ref 536797In vitro and clinical investigation of the relationship between CCR5 receptor occupancy and anti-HIV activity of Aplaviroc. J Clin Pharmacol. 2008 Oct;48(10):1179-88. Epub 2008 Aug 1.
Ref 537553Essential roles of mTOR/Akt pathway in Aurora-A cell transformation. Int J Biol Sci. 2009 Jun 19;5(5):444-50.
Ref 543547(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2053).
Ref 550422National Cancer Institute Drug Dictionary (drug id 596693).
Ref 551337he preparation and sar of 4-(anilino), 4-(phenoxy), and 4-(thiophenoxy)-quinazolines: Inhibitors of p56lck and EGF-R tyrosine kinase activity, Bioorg. Med. Chem. Lett. 7(4):417-420 (1997).
Ref 551374The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
Ref 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017

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