Pyrizolo[1,5-a]pyrimidine derivatives of the second-generation TRK inhibitor: Design, synthesis and biological evaluation.
Bioorg Med Chem Lett
; 63: 128646, 2022 05 01.
Article
em En
| MEDLINE
| ID: mdl-35231576
ABSTRACT
As a receptor tyrosine kinase (RTK), tropomyosin receptor kinase (Trk) is a key drug target in solid tumors. However, the use of the First-generation Trk inhibitors was greatly restricted due to mutant drug resistance. Fortunately, the emergence of the Second-generation of Trk inhibitors has brought an effective solution to this mutant resistance, such as TPX-0005 (Repotrectinib). Here, we reported a series of pyrizolo[1,5-a]pyrimidine derivatives as the second-generation Trk inhibitors, and carried out the subsequent biological activity evaluation. Among them, the best compound 14h (IC50 = 1.40, 1.80 nM, against TrkA, TrkAG595R, respectively) and 14j (IC50 = 0.86, 6.92 nM, against TrkA, TrkAG595R, respectively) has a kinase activity comparable to TPX-0005, and 14j (IC50 = 350 nM against ALK) has a higher selectivity of Trk inhibition than TPX-0005, which may be of great significance for reducing toxicity.
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Base de dados:
MEDLINE
Assunto principal:
Receptor trkA
/
Neoplasias
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article