2. Academic Validation
  3. Discovery of ( E)- N1-(3-Fluorophenyl)- N3-(3-(2-(pyridin-2-yl)vinyl)-1 H-indazol-6-yl)malonamide (CHMFL-KIT-033) as a Novel c-KIT T670I Mutant Selective Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)

Discovery of ( E)- N1-(3-Fluorophenyl)- N3-(3-(2-(pyridin-2-yl)vinyl)-1 H-indazol-6-yl)malonamide (CHMFL-KIT-033) as a Novel c-KIT T670I Mutant Selective Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)

  • J Med Chem. 2019 May 23;62(10):5006-5024. doi: 10.1021/acs.jmedchem.9b00176.
Xuesong Liu 1 2,  Beilei Wang 1 2,  Cheng Chen 1 2,  Ziping Qi 1 3,  Fengming Zou 1 3,  Junjie Wang 1 2,  Chen Hu 1 3,  Aoli Wang 1 3 4,  Juan Ge 1 2,  Qingwang Liu 3 4,  Kailin Yu 1 3,  Zhenquan Hu 1 3,  Zongru Jiang 1 2,  Wei Wang 1 3 4,  Li Wang 1 2,  Wenchao Wang 1 2 3 4,  Tao Ren 3 4 5,  Mingfeng Bai 6,  Qingsong Liu 1 2 3 4 7,  Jing Liu 1 2 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 , P. R. 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 Molecular Imaging Laboratory, Department of Radiology , University of Pittsburgh Cancer Institute, University of Pittsburgh , Pittsburgh , Pennsylvania 15219 , United States.
  • 7 Institutes of Physical Science and Information Technology , Anhui University , Hefei , Anhui 230601 , P. R. China.
PMID: 31046271 DOI: 10.1021/acs.jmedchem.9b00176
Abstract

Gain-of-function mutations of c-Kit kinase play crucial pathological roles for the gastrointestinal stromal tumors (GISTs). Despite the success of imatinib as the first-line treatment of GISTs, dozens of drug-acquired resistant mutations emerge, and c-Kit T670I is one of the most common mutants among them. Although several kinase inhibitors are capable of overcoming the T670I mutant, none of them can achieve the selectivity over the c-Kit wild-type (wt), which also plays important roles in a variety of physiological functions such as hematopoiesis. Starting from axitinib, through fragment hybrid type II kinase inhibitor design approach, we have discovered a novel inhibitor 24, which not only exhibits potent activity to c-Kit T670I mutant but also achieves 12-fold selectivity over c-Kit wt. Compound 24 displays good antiproliferative effects against c-Kit T670I mutant-driven GIST cell lines (GIST-T1/T670I and GIST-5R) and also exhibits suitable in vivo pharmacokinetic profiles as well as dose-dependent antitumor efficacy. This study provides a proof of concept for developing a c-Kit mutant selective inhibitor that theoretically can render a better therapeutic window.

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