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
  • 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.