Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTX41N9)

• DTT 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
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: KIT_HUMAN
• TTD ID: T57700
• 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
• 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.
• KEGG Pathway:
  Ras signaling pathway (hsa04014)
  Rap1 signaling pathway (hsa04015)
  Cytokine-cytokine receptor interaction (hsa04060)
  Endocytosis (hsa04144)
  PI3K-Akt signaling pathway (hsa04151)
  Hematopoietic cell lineage (hsa04640)
  Melanogenesis (hsa04916)
  Pathways in cancer (hsa05200)
  Acute myeloid leukemia (hsa05221)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  Regulation of KIT signaling (R-HSA-1433559)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  RAF/MAP kinase cascade (R-HSA-5673001)
  PIP3 activates AKT signaling (R-HSA-1257604)

Molecular Interaction Atlas (MIA) of This DTT

8 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[1]
Pazopanib HCl	DM6U9CQ	Renal cell carcinoma	2C90	Approved	[2]
Pexidartinib	DMS2J0Z	Tenosynovial giant cell tumour	2F7B	Approved	[3]
Ponatinib	DMYGJQO	Acute lymphoblastic leukaemia	2A85	Approved	[4]
Regorafenib	DMHSY1I	Gastrointestinal stromal tumour	2B5B	Approved	[4]
Ripretinib	DM958QB	Gastrointestinal stromal tumour	2B5B	Approved	[5]
Romiplostim	DM3U7SZ	Thrombocytopenia	3B64	Approved	[6]
Sorafenib	DMS8IFC	Adenocarcinoma	2D40	Approved	[7]

8 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Famitinib	DMSFWT7	Solid tumour/cancer	2A00-2F9Z	Phase 2	[8]
MP470	DMELUAK	Solid tumour/cancer	2A00-2F9Z	Phase 2	[9]
XL-820	DMMHX9K	Solid tumour/cancer	2A00-2F9Z	Phase 2	[10]
JSP191	DMVEYKS	Hematopoietic stem cell transplantation	QB63	Phase 1/2	[11]
PLX9486	DM5DZEL	Gastrointestinal stromal tumour	2B5B	Phase 1/2	[12]
AMG-191	DMSHK23	Inflammation	1A00-CA43.1	Phase 1	[13]
CART-117 cells	DMAKZTW	Acute myeloid leukaemia	2A60	Phase 1	[14]
OSI-930	DMF2CZ9	Solid tumour/cancer	2A00-2F9Z	Phase 1	[15]

7 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID25656651-Compound-21a	DMCKAON	N. A.	N. A.	Patented	[16]
PMID25656651-Compound-21b	DMVABXI	N. A.	N. A.	Patented	[16]
Pyridine derivative 18	DMBZMYT	N. A.	N. A.	Patented	[17]
Pyridine derivative 19	DMXYT40	N. A.	N. A.	Patented	[17]
Pyridine derivative 20	DMAOF0W	N. A.	N. A.	Patented	[17]
Pyridine derivative 21	DMF3907	N. A.	N. A.	Patented	[17]
Pyridine derivative 22	DMSIERF	N. A.	N. A.	Patented	[17]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Motesanib	DMZAL8C	Non-small-cell lung cancer	2C25.Y	Discontinued in Phase 3	[18]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CAR-T cells targeting CD117	DM9HG6S	Acute myeloid leukaemia	2A60	Preclinical	[19]

17 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4-(4-aminophenyl)-1H-indazol-3yl-amine	DMK1IWD	Discovery agent	N.A.	Investigative	[20]
5,11-Dimethyl-6H-pyrido[4,3-b]carbazol-9-ol	DMWSLTB	Discovery agent	N.A.	Investigative	[21]
9-Bromo-5,11-dimethyl-6H-pyrido[4,3-b]carbazole	DMQEO7F	Discovery agent	N.A.	Investigative	[21]
9-Methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole	DMDW267	Discovery agent	N.A.	Investigative	[21]
APCK-110	DMNQ9M1	Solid tumour/cancer	2A00-2F9Z	Investigative	[22]
AST-487	DME76KU	Discovery agent	N.A.	Investigative	[23]
Bis-(5-hydroxy-1H-indol-2-yl)-methanone	DMTSEXB	Discovery agent	N.A.	Investigative	[24]
CP-673451	DMVBPRO	Discovery agent	N.A.	Investigative	[25]
GTP-14564	DMW23Y9	Discovery agent	N.A.	Investigative	[26]
JNJ-28312141	DMCMH7O	Discovery agent	N.A.	Investigative	[27]
Ki-20227	DM9M3VC	Discovery agent	N.A.	Investigative	[28]
PD-0166326	DMD2CG9	Discovery agent	N.A.	Investigative	[29]
PD-0173956	DM8RW92	Discovery agent	N.A.	Investigative	[29]
Phosphonotyrosine	DM09MY1	Discovery agent	N.A.	Investigative	[30]
PMID22765894C8h	DMH5RFU	Discovery agent	N.A.	Investigative	[31]
PMID23521020C7k	DMPCTED	Discovery agent	N.A.	Investigative	[32]
WBZ-7	DME10AL	Solid tumour/cancer	2A00-2F9Z	Investigative	[22]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Alzheimer's disease	8A00.0	Entorhinal cortex	2.06E-01	-0.1	-0.14
Renal cancer	2C82	Kidney	5.94E-06	-1.17	-2.77
Acute myelocytic leukaemia	2C82	Bone marrow	9.88E-36	1.65	2.12
Lung cancer	2C82	Lung tissue	2.26E-22	-0.78	-1.33
Rectal cancer	2C82	Rectal colon tissue	9.00E-05	-1.49	-3.6
Breast cancer	2C82	Breast tissue	1.89E-108	-2.83	-2.3
Head and neck cancer	2C82	Head and neck tissue	1.26E-09	-0.44	-0.75
Myelodysplastic syndrome	2C82	Bone marrow	1.01E-02	0.12	0.37
Thyroid cancer	2C82	Thyroid	3.35E-88	-3.47	-5.35
Gastric cancer	2C82	Gastric tissue	3.70E-04	-1.17	-7.37
Ovarian cancer	2C82	Ovarian tissue	3.50E-04	-2.87	-1.97

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