2. Academic Validation
  3. Discovery of N-(3-((1-Isonicotinoylpiperidin-4-yl)oxy)-4-methylphenyl)-3-(trifluoromethyl)benzamide (CHMFL-KIT-110) as a Selective, Potent, and Orally Available Type II c-KIT Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)

Discovery of N-(3-((1-Isonicotinoylpiperidin-4-yl)oxy)-4-methylphenyl)-3-(trifluoromethyl)benzamide (CHMFL-KIT-110) as a Selective, Potent, and Orally Available Type II c-KIT Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)

  • J Med Chem. 2016 Apr 28;59(8):3964-79. doi: 10.1021/acs.jmedchem.6b00200.
Qiang Wang 1 2 3,  Feiyang Liu 1 4,  Beilei Wang 1 2 3,  Fengming Zou 1 2 3,  Cheng Chen 1 2 3,  Xiaochuan Liu 1 5,  Aoli Wang 1 4,  Shuang Qi 1 2 3,  Wenchao Wang 1 2 3,  Ziping Qi 1 2 3,  Zheng Zhao 1 2 3,  Zhenquan Hu 1 2 3,  Wei Wang 1 2 3,  Li Wang 1 2 3,  Shanchun Zhang 2 6,  Yuexiang Wang 7 8 9,  Jing Liu 1 2 3,  Qingsong Liu 1 2 3 4
Affiliations

Affiliations

  • 1 High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
  • 2 CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
  • 3 Center for Precision Medicine, CAS (Hefei) Institute of Technology Innovation, Hefei Institute of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China.
  • 4 University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
  • 5 Department of Chemistry, University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
  • 6 Hefei Cosource Medicine Technology Co., LTD , 358 Ganquan Road, Hefei, Anhui 230031, P. R. China.
  • 7 SIBS (Institute of Health Sciences)-Changzheng Hospital Joint Center for Translational Medicine, Institute of Health Sciences, Shanghai Changzheng Hospital, Institutes for Translational Medicine (CAS-SMMU) , Shanghai 200031, China.
  • 8 Key Laboratory of Stem Cell Biology, Institute of Health Sciences, SIBS, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine , Shanghai 200031, China.
  • 9 Collaborative Innovation Center of Systems Biomedicine , Shanghai 200025, China.
PMID: 27077705 DOI: 10.1021/acs.jmedchem.6b00200
Abstract

c-Kit kinase is a validated drug discovery target for gastrointestinal stromal tumors (GISTs). Clinically used c-Kit kinase inhibitors, i.e., Imatinib and Sunitinib, bear Other important targets such as ABL or FLT3 kinases. Here we report our discovery of a more selective c-Kit Inhibitor, compound 13 (CHMFL-KIT-110), which completely abolished ABL and FLT3 kinase activity. KinomeScan selectivity profiling (468 kinases) of 13 exhibited a high selectivity (S score (1) = 0.01). 13 displayed great antiproliferative efficacy against GISTs cell lines GIST-T1 and GIST-882 (GI50: 0.021 and 0.043 μM, respectively). In the cellular context, it effectively affected c-KIT-mediated signaling pathways and induced Apoptosis as well as cell cycle arrest. In addition, 13 possessed acceptable bioavailability (36%) and effectively suppressed the tumor growth in GIST-T1 cell inoculated xenograft model without apparent toxicity. 13 currently is undergoing extensive preclinical evaluation and might be a potential drug candidate for GISTs.

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