2. Academic Validation
  3. Discovery of 2-(4-Chloro-3-(trifluoromethyl)phenyl)- N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)acetamide (CHMFL-KIT-64) as a Novel Orally Available Potent Inhibitor against Broad-Spectrum Mutants of c-KIT Kinase for Gastrointestinal Stromal Tumors

Discovery of 2-(4-Chloro-3-(trifluoromethyl)phenyl)- N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)acetamide (CHMFL-KIT-64) as a Novel Orally Available Potent Inhibitor against Broad-Spectrum Mutants of c-KIT Kinase for Gastrointestinal Stromal Tumors

  • J Med Chem. 2019 Jul 11;62(13):6083-6101. doi: 10.1021/acs.jmedchem.9b00280.
Yun Wu 1,  Beilei Wang 1 2,  Junjie Wang 1 2,  Shuang Qi 1,  Fengming Zou 1 3 4,  Ziping Qi 1 3 4,  Feiyang Liu 1 3 4,  Qingwang Liu 3 4,  Cheng Chen 1 2,  Chen Hu 1,  Zhenquan Hu 1,  Aoli Wang 1 3 4,  Li Wang 1 2,  Wenchao Wang 1 3 4,  Tao Ren 3 4 5,  Yujiao Cai 6,  Mingfeng Bai 7,  Qingsong Liu 1 2 3 4 8,  Jing Liu 1 3 4
Affiliations

Affiliations

  • 1 High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science , Chinese Academy of Sciences , Hefei , Anhui 230031 , China.
  • 2 University of Science and Technology of China , Hefei , Anhui 230026 , P. R. China.
  • 3 Precision Medicine Research Laboratory of Anhui Province , Hefei , Anhui 230088 , 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 Precedo Pharmaceuticals Inc , Hefei , Anhui 230088 , P. R. China.
  • 6 Department of General Surgery , Second Hospital Affiliated to Army Medical University , Xinqiao Road , Chongqing 400037 , P. R. China.
  • 7 Molecular Imaging Laboratory, Department of Radiology, University of Pittsburgh Cancer Institute , University of Pittsburgh , Pittsburgh , Pennsylvania 15219 , United States.
  • 8 Institutes of Physical Science and Information Technology , Anhui University , Hefei , Anhui 230601 , P. R. China.
PMID: 31250638 DOI: 10.1021/acs.jmedchem.9b00280
Abstract

Starting from our previously developed c-Kit kinase inhibitor CHMFL-KIT-8140, through a type II kinase inhibitor binding element hybrid design approach, we discovered a novel c-Kit kinase inhibitor compound 18 (CHMFL-KIT-64), which is potent against c-Kit wt and a broad spectrum of drug-resistant mutants with improved bioavailability. 18 exhibits single-digit nM potency against c-Kit kinase and c-Kit T670I mutants in the biochemical assay and displays great potencies against most of the gain-of-function mutations in the juxtamembrane domain, drug-resistant mutations in the ATP binding pocket (except V654A), and activation loops (except D816V). In addition, 18 exhibits a good in vivo pharmacokinetic (PK) profile in different species including mice, rats, and dogs. It also displays good in vivo antitumor efficacy in the c-Kit T670I, D820G, and Y823D mutant-mediated mice models as well as in the c-Kit wt patient primary cells which are known to be imatinib-resistant. The potent activity against a broad spectrum of clinically important c-Kit mutants combining the good in vivo PK/pharmacodynamic properties of 18 indicates that it might be a new potential therapeutic candidate for gastrointestinal stromal tumors.

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