Drug-like property optimization: Discovery of orally bioavailable quinazoline-based multi-targeted kinase inhibitors.
Bioorg Chem
; 98: 103689, 2020 05.
Article
em En
| MEDLINE
| ID: mdl-32171993
ABSTRACT
In an effort to develop new cancer therapeutics, we have reported clinical candidate BPR1K871 (1) as a potentanticancercompound in MOLM-13 and MV4-11 leukemia models, as well as in colorectal and pancreatic animal models. As BPR1K871 lacks oral bioavailability, we continued searching for orally bioavailable analogs through drug-like property optimization. We optimized both the physicochemical properties (PCP) as well as in vitro rat liver microsomal stability of 1, with concomitant monitoring of aurora kinase enzyme inhibition as well as cellular anti-proliferative activity in HCT-116 cell line. Structural modification at the 6- and 7-position of quinazoline core of 1 led to the identification of 34 as an orally bioavailable (F% = 54) multi-kinase inhibitor, which exhibits potent anti-proliferative activity against various cancer cell lines. Quinazoline 34 is selected as a promising oral lead candidate for further preclinical evaluation.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinazolinas
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Inibidores de Proteínas Quinases
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Descoberta de Drogas
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Aurora Quinases
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Antineoplásicos
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Bioorg Chem
Ano de publicação:
2020
Tipo de documento:
Article