RESUMEN
Cellular and genetic evidence suggest that inhibition of ATAD2 could be a useful strategy to treat several types of cancer. To discover small-molecule inhibitors of the bromodomain of ATAD2, we used a fragment-based approach. Fragment hits were identified using NMR spectroscopy, and ATAD2 was crystallized with three of the hits identified in the fragment screen.
Asunto(s)
Adenosina Trifosfatasas/química , Química Farmacéutica/métodos , Proteínas de Unión al ADN/química , ATPasas Asociadas con Actividades Celulares Diversas , Antineoplásicos/química , Sitios de Unión , Cristalografía por Rayos X/métodos , Humanos , Cinética , Ligandos , Espectroscopía de Resonancia Magnética/métodos , Conformación Molecular , Neoplasias/tratamiento farmacológico , Estructura Terciaria de ProteínaRESUMEN
Myeloid cell leukemia 1 (Mcl-1), a member of the Bcl-2 family of proteins, is overexpressed and amplified in various cancers and promotes the aberrant survival of tumor cells that otherwise would undergo apoptosis. Here we describe the discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified two chemically distinct hit series that bind to different sites on Mcl-1. Members of the two fragment classes were merged together to produce lead compounds that bind to Mcl-1 with a dissociation constant of <100 nM with selectivity for Mcl-1 over Bcl-xL and Bcl-2. Structures of merged compounds when complexed to Mcl-1 were obtained by X-ray crystallography and provide detailed information about the molecular recognition of small-molecule ligands binding Mcl-1. The compounds represent starting points for the discovery of clinically useful Mcl-1 inhibitors for the treatment of a wide variety of cancers.
Asunto(s)
Antineoplásicos/química , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/química , Cristalografía por Rayos X , Bases de Datos Factuales , Diseño de Fármacos , Humanos , Indoles/síntesis química , Indoles/química , Ligandos , Espectroscopía de Resonancia Magnética , Simulación del Acoplamiento Molecular , Estructura Molecular , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Unión Proteica , Proteínas Proto-Oncogénicas c-bcl-2/química , Relación Estructura-Actividad , Proteína bcl-X/químicaRESUMEN
We recently described ( J. Med. Chem. 2008 , 51 , 6538 - 6546 ) a novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail SAR converting leads 1 and 2 to druglike molecules. The pivotal structural motif enabling this transition was the secondary sulfonamide substituent. Further fine-tuning of the substituent pattern in the sulfonamide paved the way to enhancing potency and bioavailability and minimizing hERG inhibition, resulting in discovery of clinical compound 122 (GSK163929).