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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.
Wang, Beilei; Zhang, Wentao; Liu, Xuesong; Zou, Fengming; Wang, Junjie; Liu, Qingwang; Wang, Aoli; Hu, Zhenquan; Chen, Yongfei; Qi, Shuang; Jiang, Zongru; Chen, Cheng; Hu, Chen; Wang, Li; Wang, Wenchao; Liu, Qingsong; Liu, Jing.
Afiliação
  • Wang B; 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
  • Zhang W; 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.
  • Liu X; 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.
  • Zou F; 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
  • Wang J; 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.
  • Liu Q; 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
  • Wang A; 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
  • Hu Z; 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.
  • Chen Y; 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
  • Qi S; 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
  • Jiang Z; 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
  • Chen C; 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.
  • Hu C; 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
  • Wang L; 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
  • Wang W; 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
  • Liu Q; 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; Prec
  • Liu J; 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
Eur J Med Chem ; 207: 112744, 2020 Dec 01.
Article em En | MEDLINE | ID: mdl-32949955
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tiazóis / Desenho de Fármacos / Resistencia a Medicamentos Antineoplásicos / Receptor trkA / Mutação Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Eur J Med Chem Ano de publicação: 2020 Tipo de documento: Article País de publicação: França
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tiazóis / Desenho de Fármacos / Resistencia a Medicamentos Antineoplásicos / Receptor trkA / Mutação Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Eur J Med Chem Ano de publicação: 2020 Tipo de documento: Article País de publicação: França