2. Academic Validation
  3. Discovery of (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide (IHMT-TRK-284) as a novel orally available type II TRK kinase inhibitor capable of overcoming multiple resistant mutants

Discovery of (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide (IHMT-TRK-284) as a novel orally available type II TRK kinase inhibitor capable of overcoming multiple resistant mutants

  • Eur J Med Chem. 2020 Dec 1;207:112744. doi: 10.1016/j.ejmech.2020.112744.
Beilei Wang 1,  Wentao Zhang 2,  Xuesong Liu 3,  Fengming Zou 1,  Junjie Wang 2,  Qingwang Liu 1,  Aoli Wang 1,  Zhenquan Hu 3,  Yongfei Chen 1,  Shuang Qi 1,  Zongru Jiang 1,  Cheng Chen 2,  Chen Hu 1,  Li Wang 1,  Wenchao Wang 1,  Qingsong Liu 4,  Jing Liu 5
Affiliations

Affiliations

  • 1 Institute of Health & Medical Technology, CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, PR China.
  • 2 Institute of Health & Medical Technology, CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui 230026, PR China.
  • 3 Institute of Health & Medical Technology, CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China.
  • 4 Institute of Health & Medical Technology, CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui 230026, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, PR China; Institute of Physical Science and Information Technology, Anhui University, Hefei, Anhui 230601, PR China. Electronic address: qsliu97@hmfl.ac.cn.
  • 5 Institute of Health & Medical Technology, CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, PR China. Electronic address: jingliu@hmfl.ac.cn.
PMID: 32949955 DOI: 10.1016/j.ejmech.2020.112744
Abstract

Due to the critical tumorigenic role of fused NTRK genes in multiple cancers, TRK kinases have attracted extensive attention as a drug discovery target. Starting from an indazole based scaffold, through the type II kinase inhibitor fragments hybrid design approach with a ring closure strategy, we discovered a novel potent type II TRK kinase inhibitor compound 34 (IHMT-TRK-284), which exhibited IC50 values of 10.5 nM, 0.7 nM and 2.6 nM to TrkA, B, and C respectively. In addition, it displayed great selectivity profile in the kinome when tested among 468 kinases and mutants (S score (1) = 0.02 at 1 μM). Importantly, 34 could overcome drug resistant mutants including V573M and F589L in the ATP binding pocket as well as G667C/S in the DFG region. In vivo, 34 exhibited good PK profiles in different species including mice, rats, and dogs. It also displayed good in vivo antitumor efficacies in the TrkA/B/C, TrkA mutants, and KM-12-LUC cells mediated mouse models. The potent activity against clinically important TRK mutants combined with the good in vivo PK and efficacy properties of 34 indicated that it might be a new potential therapeutic candidate for TRK kinase fusion or mutants driven cancers.

Keywords

Drug resistance; Kinase inhibitor; NTRK; TRK mutant.

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