Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-apoptotic Mcl-1 and Bfl-1 Proteins.
J Med Chem
; 63(5): 2489-2510, 2020 03 12.
Article
em En
| MEDLINE
| ID: mdl-31971799
ABSTRACT
Anti-apoptotic Bcl-2 family proteins are overexpressed in a wide spectrum of cancers and have become well validated therapeutic targets. Cancer cells display survival dependence on individual or subsets of anti-apoptotic proteins that could be effectively targeted by multimodal inhibitors. We designed a 2,5-substituted benzoic acid scaffold that displayed equipotent binding to Mcl-1 and Bfl-1. Structure-based design was guided by several solved cocrystal structures with Mcl-1, leading to the development of compound 24, which binds both Mcl-1 and Bfl-1 with Ki values of 100 nM and shows appreciable selectivity over Bcl-2/Bcl-xL. The selective binding profile of 24 was translated to on-target cellular activity in model lymphoma cell lines. These studies lay a foundation for developing more advanced dual Mcl-1/Bfl-1 inhibitors that have potential to provide greater single agent efficacy and broader coverage to combat resistance in several types of cancer than selective Mcl-1 inhibitors alone.
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Proto-Oncogênicas c-bcl-2
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Ácido Benzoico
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Proteína de Sequência 1 de Leucemia de Células Mieloides
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Antineoplásicos
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article