Discovery of potent Mcl-1/Bcl-xL dual inhibitors by using a hybridization strategy based on structural analysis of target proteins.
J Med Chem
; 56(23): 9635-45, 2013 Dec 12.
Article
en En
| MEDLINE
| ID: mdl-24215352
ABSTRACT
Mcl-1 and Bcl-xL are crucial regulators of apoptosis, therefore dual inhibitors of both proteins could serve as promising new anticancer drugs. To design Mcl-1/Bcl-xL dual inhibitors, we performed structure-guided analyses of the corresponding selective Mcl-1 and Bcl-xL inhibitors. A cocrystal structure of a pyrazolo[1,5-a]pyridine derivative with Mcl-1 protein was successfully determined and revealed the protein-ligand binding mode. The key structure for Bcl-xL inhibition was further confirmed through the substructural analysis of ABT-263, a representative Bcl-xL/Bcl-2/Bcl-w inhibitor developed by Abbott Laboratories. On the basis of the structural data from this analysis, we designed hybrid compounds by tethering the Mcl-1 and Bcl-xL inhibitors together. The results of X-ray crystallographic analysis of hybrid compound 10 in complexes with both Mcl-1 and Bcl-xL demonstrated its binding mode with each protein. Following further optimization, compound 11 showed potent Mcl-1/Bcl-xL dual inhibitory activity (Mcl-1, IC50 = 0.088 µM; and Bcl-xL, IC50 = 0.0037 µM).
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Sulfonamidas
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Compuestos de Bifenilo
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Apoptosis
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Proteína bcl-X
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Proteína 1 de la Secuencia de Leucemia de Células Mieloides
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Año:
2013
Tipo del documento:
Article