Target General Infomation
Target ID
T57700 (Former ID: TTDS00270)
Target Name
Tyrosine-protein kinase Kit (KIT)
Synonyms
v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog; p145 c-kit; Proto-oncogene tyrosine-protein kinase Kit; Proto-oncogene c-Kit; Piebald trait protein; PBT; Mast/stem cell growth factor receptor Kit; CD117 antigen; CD117; C-kit
Gene Name
KIT
Target Type
Successful target
[1]
Disease [+] 5 Target-related Diseases +
1 Colorectal cancer [ICD-11: 2B91]
2 Mature B-cell lymphoma [ICD-11: 2A85]
3 Myeloproliferative neoplasm [ICD-11: 2A20]
4 Renal cell carcinoma [ICD-11: 2C90]
5 Thrombocytopenia [ICD-11: 3B64]
Function
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. 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, mast cell development, migration and function, and in melanogenesis.
BioChemical Class
Kinase
UniProt ID
KIT_HUMAN
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 Modes of Action
Approved Drug(s) [+] 7 Approved Drugs +
1 Imatinib Drug Info Approved Chronic myelogenous leukaemia [2], [3]
2 Pazopanib HCl Drug Info Approved Renal cell carcinoma [4]
3 Ponatinib Drug Info Approved Acute lymphoblastic leukaemia [5], [6]
4 Regorafenib Drug Info Approved Metastatic colorectal cancer [6], [7]
5 Romiplostim Drug Info Approved Thrombocytopenia [8], [9]
6 Sorafenib Drug Info Approved Renal cell carcinoma [10], [11]
7 STI571 Drug Info Approved Acute lymphoblastic leukaemia [12], [13]
Clinical Trial Drug(s) [+] 10 Clinical Trial Drugs +
1 DCC-2618 Drug Info Phase 3 Gastrointestinal stromal tumour [14]
2 PLX-3397 Drug Info Phase 3 Alzheimer disease [15]
3 Famitinib Drug Info Phase 2 Solid tumour/cancer [16], [17]
4 MP470 Drug Info Phase 2 Solid tumour/cancer [18], [19], [20]
5 XL-820 Drug Info Phase 2 Solid tumour/cancer [21]
6 AMG-191 Drug Info Phase 1 Inflammation [22]
7 BLU-285 Drug Info Phase 1 Gastrointestinal stromal tumour [23], [14]
8 CART-117 cells Drug Info Phase 1 Myelodysplastic syndrome [24]
9 OSI-930 Drug Info Phase 1 Solid tumour/cancer [25], [26]
10 PLX9486 Drug Info Phase 1 Gastrointestinal stromal tumour [14]
Discontinued Drug(s) [+] 1 Discontinued Drugs +
1 Motesanib Drug Info Discontinued in Phase 3 Non-small-cell lung cancer [27], [28]
Preclinical Drug(s) [+] 1 Preclinical Drugs +
1 CAR-T cells targeting CD117 Drug Info Preclinical Acute myeloid leukaemia [29]
Mode of Action [+] 3 Modes of Action +
Inhibitor [+] 36 Inhibitor drugs +
1 Imatinib Drug Info [1]
2 Pazopanib HCl Drug Info [4]
3 Romiplostim Drug Info [30]
4 DCC-2618 Drug Info [23]
5 PLX-3397 Drug Info [33]
6 Famitinib Drug Info [17]
7 XL-820 Drug Info [34]
8 AMG-191 Drug Info [35]
9 BLU-285 Drug Info [14]
10 PLX9486 Drug Info [14]
11 PMID25656651-Compound-21a Drug Info [36]
12 PMID25656651-Compound-21b Drug Info [36]
13 Pyridine derivative 18 Drug Info [37]
14 Pyridine derivative 19 Drug Info [37]
15 Pyridine derivative 20 Drug Info [37]
16 Pyridine derivative 21 Drug Info [37]
17 Pyridine derivative 22 Drug Info [37]
18 Motesanib Drug Info [38], [39], [40]
19 4-(4-aminophenyl)-1H-indazol-3yl-amine Drug Info [41]
20 5,11-Dimethyl-6H-pyrido[4,3-b]carbazol-9-ol Drug Info [42]
21 9-Bromo-5,11-dimethyl-6H-pyrido[4,3-b]carbazole Drug Info [42]
22 9-Methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole Drug Info [42]
23 Adenosine-5'-Diphosphate Drug Info [32]
24 APCK-110 Drug Info [43]
25 AST-487 Drug Info [44]
26 Bis-(5-hydroxy-1H-indol-2-yl)-methanone Drug Info [45]
27 CP-673451 Drug Info [46]
28 GTP-14564 Drug Info [47]
29 JNJ-28312141 Drug Info [48]
30 Ki-20227 Drug Info [49]
31 PD-0166326 Drug Info [50]
32 PD-0173956 Drug Info [50]
33 Phosphonotyrosine Drug Info [51]
34 PMID22765894C8h Drug Info [52]
35 PMID23521020C7k Drug Info [53]
36 WBZ-7 Drug Info [43]
Modulator [+] 5 Modulator drugs +
1 Ponatinib Drug Info [12]
2 Regorafenib Drug Info [12]
3 Sorafenib Drug Info [11], [31]
4 MP470 Drug Info [19], [20]
5 OSI-930 Drug Info [25], [26]
CAR-T-Cell-Therapy [+] 2 CAR-T-Cell-Therapy drugs +
1 CART-117 cells Drug Info [24]
2 CAR-T cells targeting CD117 Drug Info [29]
Target Regulators
Target-regulating microRNAs
Target-interacting Proteins
Target Profiles in Patients
Target Expression
 Profile (TEP)
Drug Resistance
 Mutation (DRM)
Target Affiliated Biological Pathways
KEGG Pathway [+] 10 KEGG Pathways +
1 Ras signaling pathway
2 Rap1 signaling pathway
3 Cytokine-cytokine receptor interaction
4 Endocytosis
5 PI3K-Akt signaling pathway
6 Hematopoietic cell lineage
7 Melanogenesis
8 Pathways in cancer
9 Acute myeloid leukemia
10 Central carbon metabolism in cancer
NetPath Pathway [+] 3 NetPath Pathways +
1 IL3 Signaling Pathway
2 IL4 Signaling Pathway
3 KitReceptor Signaling Pathway
PID Pathway [+] 2 PID Pathways +
1 C-MYB transcription factor network
2 Signaling events mediated by Stem cell factor receptor (c-Kit)
Reactome [+] 4 Reactome Pathways +
1 PIP3 activates AKT signaling
2 Regulation of KIT signaling
3 Constitutive Signaling by Aberrant PI3K in Cancer
4 RAF/MAP kinase cascade
WikiPathways [+] 8 WikiPathways +
1 Kit receptor signaling pathway
2 Differentiation Pathway
3 Signaling by SCF-KIT
4 PIP3 activates AKT signaling
5 Cardiac Progenitor Differentiation
6 miR-targeted genes in muscle cell - TarBase
7 miR-targeted genes in lymphocytes - TarBase
8 miR-targeted genes in epithelium - TarBase
Target-Related Models and Studies
Target Validation
References
REF 1 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 2 URL: 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 3 Emerging treatments for pulmonary arterial hypertension. Expert Opin Emerg Drugs. 2006 Nov;11(4):609-19.
REF 4 Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.
REF 5 URL: 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 6 Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
REF 7 URL: 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 8 URL: 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: 6974).
REF 9 2008 FDA drug approvals. Nat Rev Drug Discov. 2009 Feb;8(2):93-6.
REF 10 URL: 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 11 Sorafenib (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 12 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 13 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006806)
REF 14 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
REF 15 ClinicalTrials.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 16 URL: 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 17 Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Br J Pharmacol. 2013 Apr;168(7):1687-706.
REF 18 URL: 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 19 Phase 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 20 The 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 21 ClinicalTrials.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 22 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029529)
REF 23 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
REF 24 ClinicalTrials.gov (NCT03291444) CAR-T Cells Combined With Peptide Specific Dendritic Cell in Relapsed/Refractory Leukemia/MDS
REF 25 OSI-930 analogues as novel reversal agents for ABCG2-mediated multidrug resistance. Biochem Pharmacol. 2012 Sep 15;84(6):766-74.
REF 26 Inhibition 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 27 URL: 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 28 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800011016)
REF 29 ClinicalTrials.gov (NCT03473457) CAR-T Cells Therapy in Relapsed/Refractory Acute Myeloid Leukemia
REF 30 New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven a... J Med Chem. 2000 Jun 15;43(12):2310-23.
REF 31 Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling.Mol Cancer Ther.2008 Oct;7(10):3129-40.
REF 32 DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.
REF 33 National Cancer Institute Drug Dictionary (drug id 659167).
REF 34 National Cancer Institute Drug Dictionary (drug id 452042).
REF 35 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029529)
REF 36 Bcr-Abl tyrosine kinase inhibitors: a patent review.Expert Opin Ther Pat. 2015 Apr;25(4):397-412.
REF 37 RET kinase inhibitors: a review of recent patents (2012-2015).Expert Opin Ther Pat. 2017 Jan;27(1):91-99.
REF 38 Clinical pipeline report, company report or official report of Amgen (2009).
REF 39 Phase 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.
REF 40 Axitinib for renal cell carcinoma. Expert Opin Investig Drugs. 2008 May;17(5):741-8.
REF 41 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 ... J Med Chem. 2007 Apr 5;50(7):1584-97.
REF 42 Molecular modeling of wild-type and D816V c-Kit inhibition based on ATP-competitive binding of ellipticine derivatives to tyrosine kinases. J Med Chem. 2005 Oct 6;48(20):6194-201.
REF 43 URL: 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 44 The 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 45 Novel bis(1H-indol-2-yl)methanones as potent inhibitors of FLT3 and platelet-derived growth factor receptor tyrosine kinase. J Med Chem. 2006 Jun 1;49(11):3101-15.
REF 46 Antiangiogenic and antitumor activity of a selective PDGFR tyrosine kinase inhibitor, CP-673,451. Cancer Res. 2005 Feb 1;65(3):957-66.
REF 47 Selective cytotoxic mechanism of GTP-14564, a novel tyrosine kinase inhibitor in leukemia cells expressing a constitutively active Fms-like tyrosin... J Biol Chem. 2003 Aug 29;278(35):32892-8.
REF 48 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 49 A 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 50 Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones: toward selective Abl inhibitors. Bioorg Med Chem Lett. 2009 Dec 15;19(24):6872-6.
REF 51 How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
REF 52 The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2012 Aug 1;22(15):4979-85.
REF 53 Discovery 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.

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