Target Information

Target General Infomation
Target ID
T57700
Former ID
TTDS00270
Target Name
Mast/stem cell growth factor receptor
Gene Name
KIT
Synonyms
C-kit; CD117 antigen; Proto-oncogene tyrosine-protein kinase Kit; SCFR; KIT
Target Type
Successful
Disease Acute lymphoblastic leukemia [ICD9: 204.0, 556; ICD10: C91.0]
Advanced renal cell carcinoma [ICD9: 189; ICD10: C64]
Alzheimer disease [ICD9: 331; ICD10: G30]
Chronic myelogenous leukaemia [ICD9: 205.1; ICD10: C92.1]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Glioma; Lung cancer; Prostate cancer; Solid tumours [ICD9: 140-199, 191, 210-229; ICD10: C00-C75, C71, C7A, C7B, D10-D36, D3A]
Hepatocellular carcinoma; NSCLC; Melanoma [ICD9: 155, 162, 172; ICD10: C22.0, C33, C34, C43]
Intestinal cancer; Myeloid leukemia [ICD9: 152, 153, 205; ICD10: C17, C18, C92]
Inflammatory disease [ICD9: 140-229, 147, 173, 573.3, 710-719; ICD10: C11, C44, K75.9, M00-M25]
Myelodysplastic syndrome; AML; Head and neck cancer; Breast cancer; Pancreatic cancer [ICD9: 140-149, 140-229, 157, 183, 205.0; ICD10: C07-C14, C25, C32, C33, C56, C92.0]
Metastatic colorectal cancer [ICD9: 153, 154; ICD10: C18-C21]
Non-small cell lung cancer [ICD10: C33-C34]
Renal cancer [ICD9: 140-229, 189; ICD10: C64]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Function
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mastcell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1.
BioChemical Class
Kinase
Target Validation
T57700
UniProt ID
P10721
EC Number
EC 2.7.10.1
Sequence
MRGARGAWDFLCVLLLLLRVQTGSSQPSVSPGEPSPPSIHPGKSDLIVRVGDEIRLLCTD
PGFVKWTFEILDETNENKQNEWITEKAEATNTGKYTCTNKHGLSNSIYVFVRDPAKLFLV
DRSLYGKEDNDTLVRCPLTDPEVTNYSLKGCQGKPLPKDLRFIPDPKAGIMIKSVKRAYH
RLCLHCSVDQEGKSVLSEKFILKVRPAFKAVPVVSVSKASYLLREGEEFTVTCTIKDVSS
SVYSTWKRENSQTKLQEKYNSWHHGDFNYERQATLTISSARVNDSGVFMCYANNTFGSAN
VTTTLEVVDKGFINIFPMINTTVFVNDGENVDLIVEYEAFPKPEHQQWIYMNRTFTDKWE
DYPKSENESNIRYVSELHLTRLKGTEGGTYTFLVSNSDVNAAIAFNVYVNTKPEILTYDR
LVNGMLQCVAAGFPEPTIDWYFCPGTEQRCSASVLPVDVQTLNSSGPPFGKLVVQSSIDS
SAFKHNGTVECKAYNDVGKTSAYFNFAFKGNNKEQIHPHTLFTPLLIGFVIVAGMMCIIV
MILTYKYLQKPMYEVQWKVVEEINGNNYVYIDPTQLPYDHKWEFPRNRLSFGKTLGAGAF
GKVVEATAYGLIKSDAAMTVAVKMLKPSAHLTEREALMSELKVLSYLGNHMNIVNLLGAC
TIGGPTLVITEYCCYGDLLNFLRRKRDSFICSKQEDHAEAALYKNLLHSKESSCSDSTNE
YMDMKPGVSYVVPTKADKRRSVRIGSYIERDVTPAIMEDDELALDLEDLLSFSYQVAKGM
AFLASKNCIHRDLAARNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLPVKWMAPES
IFNCVYTFESDVWSYGIFLWELFSLGSSPYPGMPVDSKFYKMIKEGFRMLSPEHAPAEMY
DIMKTCWDADPLKRPTFKQIVQLIEKQISESTNHIYSNLANCSPNRQKPVVDHSVRINSV
GSTASSSQPLLVHDDV
Drugs and Mode of Action
Drug(s) Imatinib Drug Info Approved Chronic myelogenous leukaemia [536294], [541030]
Pazopanib HCl Drug Info Approved Renal cancer [530677]
Ponatinib Drug Info Approved Acute lymphoblastic leukemia [532210], [541188]
Regorafenib Drug Info Approved Metastatic colorectal cancer [532210], [541189]
Sorafenib Drug Info Approved Advanced renal cell carcinoma [528230], [541050]
Imatinib Drug Info Phase 3 Intestinal cancer; Myeloid leukemia [536294], [541030]
PLX-3397 Drug Info Phase 3 Alzheimer disease [525099]
Sorafenib Drug Info Phase 3 Hepatocellular carcinoma; NSCLC; Melanoma [537114], [541050]
Famitinib Drug Info Phase 2 Cancer [532104], [542811]
Imatinib Drug Info Phase 2 Glioma; Lung cancer; Prostate cancer; Solid tumours [536294], [541030]
MP470 Drug Info Phase 2 Solid tumours [531617], [532785], [542847]
Sorafenib Drug Info Phase 2 Myelodysplastic syndrome; AML; Head and neck cancer; Breast cancer; Pancreatic cancer [537114], [541050]
XL-820 Drug Info Phase 2 Solid tumours [522178]
AMG-191 Drug Info Phase 1 Inflammatory disease [548849]
OSI-930 Drug Info Phase 1 Solid tumours [531624], [531955]
Motesanib Drug Info Discontinued in Phase 3 Non-small cell lung cancer [541005], [546905]
Inhibitor 4-(4-aminophenyl)-1H-indazol-3yl-amine Drug Info [528716]
5,11-Dimethyl-6H-pyrido[4,3-b]carbazol-9-ol Drug Info [527769]
9-Bromo-5,11-dimethyl-6H-pyrido[4,3-b]carbazole Drug Info [527769]
9-Methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole Drug Info [527769]
Adenosine-5'-Diphosphate Drug Info [551391]
AMG-191 Drug Info [548850]
APCK-110 Drug Info [543493]
AST-487 Drug Info [528954]
Bis-(5-hydroxy-1H-indol-2-yl)-methanone Drug Info [528209]
compound 7k Drug Info [532280]
compound 8h Drug Info [531959]
CP-673451 Drug Info [527429]
Famitinib Drug Info [532104]
GTP-14564 Drug Info [526648]
Imatinib Drug Info [536474]
JNJ-28312141 Drug Info [530495]
Ki-20227 Drug Info [528535]
Motesanib Drug Info [537551], [550250], [551087]
Pazopanib HCl Drug Info [530677]
PD-0166326 Drug Info [530497]
PD-0173956 Drug Info [530497]
Phosphonotyrosine Drug Info [551393]
PLX-3397 Drug Info [550447]
SEMAXINIB Drug Info [525812]
WBZ-7 Drug Info [543493]
XL-820 Drug Info [550402]
Modulator MP470 Drug Info [531617], [532785]
OSI-930 Drug Info [531624], [531955]
Ponatinib Drug Info [551871]
Regorafenib Drug Info [551871]
Sorafenib Drug Info [528230]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
DRM DRM Info
Pathways
KEGG Pathway Ras signaling pathway
Rap1 signaling pathway
Cytokine-cytokine receptor interaction
Endocytosis
PI3K-Akt signaling pathway
Hematopoietic cell lineage
Melanogenesis
Pathways in cancer
Acute myeloid leukemia
Central carbon metabolism in cancer
NetPath Pathway IL3 Signaling Pathway
IL4 Signaling Pathway
KitReceptor Signaling Pathway
Pathway Interaction Database C-MYB transcription factor network
Signaling events mediated by Stem cell factor receptor (c-Kit)
Reactome PIP3 activates AKT signaling
Regulation of KIT signaling
Constitutive Signaling by Aberrant PI3K in Cancer
RAF/MAP kinase cascade
WikiPathways Kit receptor signaling pathway
Differentiation Pathway
Signaling by SCF-KIT
PIP3 activates AKT signaling
Cardiac Progenitor Differentiation
miR-targeted genes in muscle cell - TarBase
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in epithelium - TarBase
References
Ref 522178ClinicalTrials.gov (NCT00570635) A Phase 2 Study of XL820 in Adults With Advanced GIST Resistant to Imatinib and/or Sunitinib. U.S. National Institutes of Health.
Ref 525099ClinicalTrials.gov (NCT02371369) PLX3397 Phase 3 Study for Pigmented Villonodular Synovitis (PVNS) or Giant Cell Tumor of the Tendon Sheath (GCT-TS). U.S. National Institutes of Health.
Ref 528230Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol. 2006;407:597-612.
Ref 530677Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.
Ref 531617The receptor tyrosine kinase inhibitor amuvatinib (MP470) sensitizes tumor cells to radio- and chemo-therapies in part by inhibiting homologous recombination. Radiother Oncol. 2011 Oct;101(1):59-65.
Ref 531624Inhibition of c-Kit, VEGFR-2 (KDR), and ABCG2 by analogues of OSI-930. Bioorg Med Chem Lett. 2011 Nov 1;21(21):6495-9.
Ref 531955OSI-930 analogues as novel reversal agents for ABCG2-mediated multidrug resistance. Biochem Pharmacol. 2012 Sep 15;84(6):766-74.
Ref 532104Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Br J Pharmacol. 2013 Apr;168(7):1687-706.
Ref 532210Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
Ref 532785Phase 1B study of amuvatinib in combination with five standard cancer therapies in adults with advanced solid tumors. Cancer Chemother Pharmacol. 2014 Jul;74(1):195-204.
Ref 536294Emerging treatments for pulmonary arterial hypertension. Expert Opin Emerg Drugs. 2006 Nov;11(4):609-19.
Ref 537114Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
Ref 541005(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: 5660).
Ref 541030(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: 5687).
Ref 541050(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: 5711).
Ref 541188(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: 5890).
Ref 541189(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: 5891).
Ref 542811(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: 7886).
Ref 542847(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: 7932).
Ref 546905Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800011016)
Ref 548849Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029529)
Ref 525812J Med Chem. 2000 Jun 15;43(12):2310-23.New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis.
Ref 526648Selective cytotoxic mechanism of GTP-14564, a novel tyrosine kinase inhibitor in leukemia cells expressing a constitutively active Fms-like tyrosine kinase 3 (FLT3). J Biol Chem. 2003 Aug 29;278(35):32892-8. Epub 2003 Jun 18.
Ref 527429Antiangiogenic and antitumor activity of a selective PDGFR tyrosine kinase inhibitor, CP-673,451. Cancer Res. 2005 Feb 1;65(3):957-66.
Ref 527769J Med Chem. 2005 Oct 6;48(20):6194-201.Molecular modeling of wild-type and D816V c-Kit inhibition based on ATP-competitive binding of ellipticine derivatives to tyrosine kinases.
Ref 528209J Med Chem. 2006 Jun 1;49(11):3101-15.Novel bis(1H-indol-2-yl)methanones as potent inhibitors of FLT3 and platelet-derived growth factor receptor tyrosine kinase.
Ref 528230Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol. 2006;407:597-612.
Ref 528535A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol Cancer Ther. 2006 Nov;5(11):2634-43.
Ref 528716J Med Chem. 2007 Apr 5;50(7):1584-97. Epub 2007 Mar 8.Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor.
Ref 528954The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells. Cancer Res. 2007 Jul 15;67(14):6956-64.
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 530497Bioorg Med Chem Lett. 2009 Dec 15;19(24):6872-6. Epub 2009 Oct 23.Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones: toward selective Abl inhibitors.
Ref 530677Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.
Ref 531617The receptor tyrosine kinase inhibitor amuvatinib (MP470) sensitizes tumor cells to radio- and chemo-therapies in part by inhibiting homologous recombination. Radiother Oncol. 2011 Oct;101(1):59-65.
Ref 531624Inhibition of c-Kit, VEGFR-2 (KDR), and ABCG2 by analogues of OSI-930. Bioorg Med Chem Lett. 2011 Nov 1;21(21):6495-9.
Ref 531955OSI-930 analogues as novel reversal agents for ABCG2-mediated multidrug resistance. Biochem Pharmacol. 2012 Sep 15;84(6):766-74.
Ref 531959The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2012 Aug 1;22(15):4979-85.
Ref 532104Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Br J Pharmacol. 2013 Apr;168(7):1687-706.
Ref 532280Discovery and optimization of 3-(2-(Pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamides as novel selective and orally bioavailable discoidin domain receptor 1 (DDR1) inhibitors. J Med Chem. 2013 Apr 25;56(8):3281-95.
Ref 532785Phase 1B study of amuvatinib in combination with five standard cancer therapies in adults with advanced solid tumors. Cancer Chemother Pharmacol. 2014 Jul;74(1):195-204.
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 537551Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol. 2009 Aug 10;27(23):3794-801. Epub 2009 Jun 29.
Ref 543493(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: 1805).
Ref 548850Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029529)
Ref 550250Clinical pipeline report, company report or official report of Amgen (2009).
Ref 550402National Cancer Institute Drug Dictionary (drug id 452042).
Ref 550447National Cancer Institute Drug Dictionary (drug id 659167).
Ref 551087Axitinib for renal cell carcinoma. Expert Opin Investig Drugs. 2008 May;17(5):741-8.
Ref 551391DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-4. Nucleic Acids Res. 2011 January
Ref 551393How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
Ref 551871Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
Ref 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017

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