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
; 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.
Palavras-chave
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