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. Epub 2016 Aug 30.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry*
  • Amides / pharmacokinetics
  • Amides / pharmacology
  • Amides / therapeutic use*
  • Animals
  • Cell Line, Tumor
  • Female
  • Gastrointestinal Neoplasms / drug therapy*
  • Gastrointestinal Neoplasms / genetics
  • Gastrointestinal Neoplasms / metabolism
  • Gastrointestinal Neoplasms / pathology
  • Gastrointestinal Stromal Tumors / drug therapy*
  • Gastrointestinal Stromal Tumors / genetics
  • Gastrointestinal Stromal Tumors / metabolism
  • Gastrointestinal Stromal Tumors / pathology
  • Gastrointestinal Tract / drug effects
  • Gastrointestinal Tract / metabolism
  • Gastrointestinal Tract / pathology
  • Halogenation
  • Humans
  • Methylation
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Mutation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins c-kit / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-kit / genetics
  • Proto-Oncogene Proteins c-kit / metabolism
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Amides
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-kit
  • propionamide