Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity.
J Med Chem
; 58(5): 2180-94, 2015 Mar 12.
Article
em En
| MEDLINE
| ID: mdl-25679114
ABSTRACT
Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report a series of MCL-1 inhibitors that emanated from a high throughput screening (HTS) hit and progressed via iterative cycles of structure-guided design. Advanced compounds from this series exhibited subnanomolar affinity for MCL-1 and excellent selectivity over other BCL-2 family proteins as well as multiple kinases and GPCRs. In a MCL-1 dependent human tumor cell line, administration of compound 30b rapidly induced caspase activation with associated loss in cell viability. The small molecules described herein thus comprise effective tools for studying MCL-1 biology.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
/
Desenho de Fármacos
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Proteína de Sequência 1 de Leucemia de Células Mieloides
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Mieloma Múltiplo
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Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Estados Unidos