Target Information
Target General Infomation | |||||
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Target ID |
T12499
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Former ID |
TTDS00407
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Target Name |
Lck tyrosine kinase
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Gene Name |
LCK
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Synonyms |
FYN; Protooncogene Syn; SLK; p59-Fyn; Proto-oncogene tyrosine-protein kinase LCK; LCK
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Target Type |
Successful
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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}.
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BioChemical Class |
Kinase
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Target Validation |
T12499
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UniProt ID | |||||
EC Number |
EC 2.7.10.2
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Sequence |
MGCGCSSHPEDDWMENIDVCENCHYPIVPLDGKGTLLIRNGSEVRDPLVTYEGSNPPASP
LQDNLVIALHSYEPSHDGDLGFEKGEQLRILEQSGEWWKAQSLTTGQEGFIPFNFVAKAN SLEPEPWFFKNLSRKDAERQLLAPGNTHGSFLIRESESTAGSFSLSVRDFDQNQGEVVKH YKIRNLDNGGFYISPRITFPGLHELVRHYTNASDGLCTRLSRPCQTQKPQKPWWEDEWEV PRETLKLVERLGAGQFGEVWMGYYNGHTKVAVKSLKQGSMSPDAFLAEANLMKQLQHQRL VRLYAVVTQEPIYIITEYMENGSLVDFLKTPSGIKLTINKLLDMAAQIAEGMAFIEERNY IHRDLRAANILVSDTLSCKIADFGLARLIEDNEYTAREGAKFPIKWTAPEAINYGTFTIK SDVWSFGILLTEIVTHGRIPYPGMTNPEVIQNLERGYRMVRPDNCPEELYQLMRLCWKER PEDRPTFDYLRSVLEDFFTATEGQYQPQP |
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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
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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& | |||||
#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& | |||||
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 521505 | ClinicalTrials.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 522319 | ClinicalTrials.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 526974 | Nat 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 536577 | Dasatinib: 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 536957 | Current 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 525862 | Biochem 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 525872 | Biochem J. 2000 Oct 1;351(Pt 1):95-105.Specificity and mechanism of action of some commonly used protein kinase inhibitors. | ||||
Ref 525876 | Bioorg 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 525877 | Pyrrolo[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 527057 | Bioorg 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 527295 | Discovery 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 527308 | J Med Chem. 2004 Dec 2;47(25):6239-47.Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. | ||||
Ref 527421 | J Med Chem. 2005 Feb 10;48(3):710-22.Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors. | ||||
Ref 527711 | J 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 527790 | Bioorg 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 527836 | Bioorg 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 527932 | J 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 528108 | J 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 528352 | Novel 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 528429 | J 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 528527 | Bioorg 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 528657 | 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. 2007 Apr 15;17(8):2305-9. Epub 2007 Jan 25. | ||||
Ref 528928 | Bioorg 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 529039 | Biochem J. 2007 Dec 15;408(3):297-315.The selectivity of protein kinase inhibitors: a further update. | ||||
Ref 529647 | J 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 530495 | 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. 2009 Nov;8(11):3151-61. | ||||
Ref 531604 | Discovery 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 531860 | X-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 533795 | J Med Chem. 1993 Nov 12;36(23):3556-64.Tyrphostins. 3. Structure-activity relationship studies of alpha-substituted benzylidenemalononitrile 5-S-aryltyrphostins. | ||||
Ref 533899 | J Med Chem. 1993 Oct 1;36(20):3010-4.Non-amine based analogues of lavendustin A as protein-tyrosine kinase inhibitors. | ||||
Ref 534651 | J 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 536331 | Multi-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 536474 | A 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 536797 | In 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 537553 | Essential 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). |
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