2. Academic Validation
  3. Discovery of N-((1-(4-(3-(3-((6,7-Dimethoxyquinolin-3-yl)oxy)phenyl)ureido)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)propionamide (CHMFL-KIT-8140) as a Highly Potent Type II Inhibitor Capable of Inhibiting the T670I "Gatekeeper" Mutant of cKIT Kinase

Discovery of N-((1-(4-(3-(3-((6,7-Dimethoxyquinolin-3-yl)oxy)phenyl)ureido)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)propionamide (CHMFL-KIT-8140) as a Highly Potent Type II Inhibitor Capable of Inhibiting the T670I "Gatekeeper" Mutant of cKIT Kinase

  • J Med Chem. 2016 Sep 22;59(18):8456-72. doi: 10.1021/acs.jmedchem.6b00902.
Binhua Li 1 2,  Aoli Wang 1 3,  Juan Liu 1,  Ziping Qi 1 2,  Xiaochuan Liu 1,  Kailin Yu 1 3,  Hong Wu 1,  Cheng Chen 1 2,  Chen Hu 1 3,  Wenchao Wang 1 2,  Jiaxin Wu 1 3,  Zhenquan Hu 1 2,  Ling Ye 4,  Fengming Zou 1 2,  Feiyang Liu 1 3,  Beilei Wang 1 2,  Li Wang 1 2,  Tao Ren 4,  Shaojuan Zhang 5 6 7,  Mingfeng Bai 5 6 7,  Shanchun Zhang 2 8,  Jing Liu 1 2,  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 University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
  • 4 Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China.
  • 5 Molecular Imaging Laboratory, Department of Radiology, University of Pittsburgh , Pittsburgh, Pennsylvania 15219, United States.
  • 6 Department of Bioengineering, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.
  • 7 University of Pittsburgh Cancer Institute , Pittsburgh, Pennsylvania 15232, United States.
  • 8 Hefei Cosource Medicine Technology Co. LTD. , 358 Ganquan Road, Hefei, Anhui 230031, P. R. China.
PMID: 27545040 DOI: 10.1021/acs.jmedchem.6b00902
Abstract

cKIT kinase inhibitors, e.g., imatinib, could induce drug-acquired mutations such as cKIT T670I that rendered drug resistance after chronic treatment. Through a type II kinase inhibitor design approach we discovered a highly potent type II cKIT kinase inhibitor compound 35 (CHMFL-KIT-8140), which potently inhibited both cKIT wt (IC50 = 33 nM) and cKIT gatekeeper T670I mutant (IC50 = 99 nM). Compound 35 displayed strong antiproliferative effect against GISTs Cancer cell lines GIST-T1 (cKIT wt, GI50 = 4 nM) and GIST-5R (cKIT T670I, GI50 = 26 nM). In the cellular context it strongly inhibited c-Kit mediated signaling pathways and induced Apoptosis. In the BaF3-TEL-cKIT-T670I isogenic cell inoculated xenograft mouse model, 35 exhibited dose dependent tumor growth suppression efficacy and 100 mg/kg dosage provided 47.7% tumor growth inhibition (TGI) without obvious toxicity. We believe compound 35 would be a good pharmacological tool for exploration of the cKIT-T670I mutant mediated pathology in GISTs.

Figures
Products