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J Med Chem ; 64(14): 10102-10123, 2021 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-34255515

RESUMEN

CREBBP (CBP/KAT3A) and its paralogue EP300 (KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. They each comprise 10 domains through which they interact with >400 proteins, making them important transcriptional co-activators and key nodes in the human protein-protein interactome. The bromodomains of CREBBP and EP300 enable the binding of acetylated lysine residues from histones and a number of other important proteins, including p53, p73, E2F, and GATA1. Here, we report a work to develop a high-affinity, small-molecule ligand for the CREBBP and EP300 bromodomains [(-)-OXFBD05] that shows >100-fold selectivity over a representative member of the BET bromodomains, BRD4(1). Cellular studies using this ligand demonstrate that the inhibition of the CREBBP/EP300 bromodomain in HCT116 colon cancer cells results in lowered levels of c-Myc and a reduction in H3K18 and H3K27 acetylation. In hypoxia (<0.1% O2), the inhibition of the CREBBP/EP300 bromodomain results in the enhanced stabilization of HIF-1α.


Asunto(s)
Benzodiazepinonas/farmacología , Proteína de Unión a CREB/antagonistas & inhibidores , Diseño de Fármacos , Proteína p300 Asociada a E1A/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Benzodiazepinonas/síntesis química , Benzodiazepinonas/química , Proteína de Unión a CREB/metabolismo , Relación Dosis-Respuesta a Droga , Proteína p300 Asociada a E1A/metabolismo , Células HCT116 , Humanos , Ligandos , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad
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