Discovery of novel indazole-acylsulfonamide hybrids as selective Mcl-1 inhibitors.
Bioorg Chem
; 104: 104217, 2020 11.
Article
em En
| MEDLINE
| ID: mdl-32911192
ABSTRACT
Overexpressing myeloid cell leukemia sequence 1 (Mcl-1) protein is an important way to confer the resistance of cancer cells to conventional anti-cancer treatments. Therefore, developing Mcl-1 inhibitors has become an attractive strategy for cancer therapy. In the studies, a series of new indazole-acylsulfonamide hybrids were designed, synthesized and evaluated as potent Mcl-1 inhibitors. Among them, the most potent compound 17 (Ki = 0.43 µM) showed a little better inhibitory activity against Mcl-1 protein than positive control AT-101 (Ki = 0.45 µM). Pleasingly, it displayed > 40-fold selectivity over Bcl-2 (Ki = 18 µM) and Bcl-xL (no activity). Furthermore, compound 17 had good inhibitory activities against PC-3, MDA-MB-231 and K562 cells (IC50 = 12.3, 10.6 and 6.62 µM, respectively) and could effectively induce apoptosis and the activation of caspase-3 in a dose-dependent manner in K562 cells.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Sulfonamidas
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Descoberta de Drogas
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Proteína de Sequência 1 de Leucemia de Células Mieloides
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Indazóis
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Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article