Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHUY3VZ)

• DOT Name: Mast/stem cell growth factor receptor Kit (KIT)
• Synonyms: SCFR; EC 2.7.10.1; Piebald trait protein; PBT; Proto-oncogene c-Kit; Tyrosine-protein kinase Kit; p145 c-kit; v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog; CD antigen CD117
• Gene Name: KIT
• Related Disease:
  Gastrointestinal stromal tumour
  Piebaldism
  Cutaneous mastocytosis
  Mastocytosis
• UniProt ID: KIT_HUMAN
• PDB ID: 1PKG ; 1T45 ; 1T46 ; 2E9W ; 2EC8 ; 2IUH ; 2VIF ; 3G0E ; 3G0F ; 4HVS ; 4K94 ; 4K9E ; 4PGZ ; 4U0I ; 6GQJ ; 6GQK ; 6GQL ; 6GQM ; 6HH1 ; 6ITT ; 6ITV ; 6KLA ; 6MOB ; 6XV9 ; 6XVA ; 6XVB ; 7KHG ; 7KHJ ; 7KHK ; 7ZW8 ; 7ZY6 ; 8DFM ; 8DFP ; 8DFQ
• EC Number: 2.7.10.1
• Pfam ID: PF00047 ; PF07714
• Sequence:
  MRGARGAWDFLCVLLLLLRVQTGSSQPSVSPGEPSPPSIHPGKSDLIVRVGDEIRLLCTD
  PGFVKWTFEILDETNENKQNEWITEKAEATNTGKYTCTNKHGLSNSIYVFVRDPAKLFLV
  DRSLYGKEDNDTLVRCPLTDPEVTNYSLKGCQGKPLPKDLRFIPDPKAGIMIKSVKRAYH
  RLCLHCSVDQEGKSVLSEKFILKVRPAFKAVPVVSVSKASYLLREGEEFTVTCTIKDVSS
  SVYSTWKRENSQTKLQEKYNSWHHGDFNYERQATLTISSARVNDSGVFMCYANNTFGSAN
  VTTTLEVVDKGFINIFPMINTTVFVNDGENVDLIVEYEAFPKPEHQQWIYMNRTFTDKWE
  DYPKSENESNIRYVSELHLTRLKGTEGGTYTFLVSNSDVNAAIAFNVYVNTKPEILTYDR
  LVNGMLQCVAAGFPEPTIDWYFCPGTEQRCSASVLPVDVQTLNSSGPPFGKLVVQSSIDS
  SAFKHNGTVECKAYNDVGKTSAYFNFAFKGNNKEQIHPHTLFTPLLIGFVIVAGMMCIIV
  MILTYKYLQKPMYEVQWKVVEEINGNNYVYIDPTQLPYDHKWEFPRNRLSFGKTLGAGAF
  GKVVEATAYGLIKSDAAMTVAVKMLKPSAHLTEREALMSELKVLSYLGNHMNIVNLLGAC
  TIGGPTLVITEYCCYGDLLNFLRRKRDSFICSKQEDHAEAALYKNLLHSKESSCSDSTNE
  YMDMKPGVSYVVPTKADKRRSVRIGSYIERDVTPAIMEDDELALDLEDLLSFSYQVAKGM
  AFLASKNCIHRDLAARNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLPVKWMAPES
  IFNCVYTFESDVWSYGIFLWELFSLGSSPYPGMPVDSKFYKMIKEGFRMLSPEHAPAEMY
  DIMKTCWDADPLKRPTFKQIVQLIEKQISESTNHIYSNLANCSPNRQKPVVDHSVRINSV
  GSTASSSQPLLVHDDV
• Function: Tyrosine-protein kinase that acts as a 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. 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.
• Tissue Specificity: .In testis, detected in spermatogonia in the basal layer and in interstitial Leydig cells but not in Sertoli cells or spermatocytes inside the seminiferous tubules (at protein level) . Expression is maintained in ejaculated spermatozoa (at protein level) .
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Phospholipase D sig.ling pathway (hsa04072)
  PI3K-Akt sig.ling pathway (hsa04151)
  Hematopoietic cell lineage (hsa04640)
  Melanogenesis (hsa04916)
  Pathways in cancer (hsa05200)
  Acute myeloid leukemia (hsa05221)
  Breast cancer (hsa05224)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  Signaling by SCF-KIT (R-HSA-1433557)
  Regulation of KIT signaling (R-HSA-1433559)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  RAF/MAP kinase cascade (R-HSA-5673001)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  TFAP2 (AP-2) family regulates transcription of growth factors and their receptors (R-HSA-8866910)
  Dasatinib-resistant KIT mutants (R-HSA-9669914)
  Imatinib-resistant KIT mutants (R-HSA-9669917)
  KIT mutants bind TKIs (R-HSA-9669921)
  Masitinib-resistant KIT mutants (R-HSA-9669924)
  Nilotinib-resistant KIT mutants (R-HSA-9669926)
  Regorafenib-resistant KIT mutants (R-HSA-9669929)
  Signaling by kinase domain mutants of KIT (R-HSA-9669933)
  Sunitinib-resistant KIT mutants (R-HSA-9669934)
  Signaling by juxtamembrane domain KIT mutants (R-HSA-9669935)
  Sorafenib-resistant KIT mutants (R-HSA-9669936)
  Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants (R-HSA-9670439)
  Signaling by extracellular domain mutants of KIT (R-HSA-9680187)
  PIP3 activates AKT signaling (R-HSA-1257604)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastrointestinal stromal tumour	DIS6TJYS	Definitive	Autosomal dominant	[1]
Piebaldism	DISDLDF2	Definitive	Autosomal dominant	[2]
Cutaneous mastocytosis	DISLBZEF	Strong	Autosomal dominant	[3]
Mastocytosis	DIS1TEE0	Strong	Autosomal dominant	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Crizotinib	DM4F29C	Approved	Mast/stem cell growth factor receptor Kit (KIT) decreases the response to substance of Crizotinib.	[36]

29 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[12]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[15]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[16]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[19]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol affects the expression of Mast/stem cell growth factor receptor Kit (KIT).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[12]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[21]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin decreases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[22]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[23]
Flavopiridol	DMKSUOI	Phase 2	Flavopiridol decreases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[24]
NVP-AUY922	DMTYXQF	Phase 2	NVP-AUY922 decreases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[25]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Mast/stem cell growth factor receptor Kit (KIT).	[27]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[28]
Pifithrin-alpha	DM63OD7	Terminated	Pifithrin-alpha decreases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[30]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[31]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[32]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[33]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[34]
Ginsenoside RG3	DMFN58T	Investigative	Ginsenoside RG3 decreases the expression of Mast/stem cell growth factor receptor Kit (KIT).	[35]

5 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Mast/stem cell growth factor receptor Kit (KIT).	[14]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the phosphorylation of Mast/stem cell growth factor receptor Kit (KIT).	[17]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the phosphorylation of Mast/stem cell growth factor receptor Kit (KIT).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Mast/stem cell growth factor receptor Kit (KIT).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Mast/stem cell growth factor receptor Kit (KIT).	[14]

References

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