Structure-Based Design of Highly Selective Inhibitors of the CREB Binding Protein Bromodomain.
Rajiah Aldrin DennyAndrew C FlickJotham CoeJonathan LangilleArindrajit BasakShenping LiuIngrid StockParag SahasrabudhePaul BoninDuncan A HayPaul E BrennanMathew PletcherLyn H JonesEugene L Piatnitski CheklerPublished in: Journal of medicinal chemistry (2017)
Chemical probes are required for preclinical target validation to interrogate novel biological targets and pathways. Selective inhibitors of the CREB binding protein (CREBBP)/EP300 bromodomains are required to facilitate the elucidation of biology associated with these important epigenetic targets. Medicinal chemistry optimization that paid particular attention to physiochemical properties delivered chemical probes with desirable potency, selectivity, and permeability attributes. An important feature of the optimization process was the successful application of rational structure-based drug design to address bromodomain selectivity issues (particularly against the structurally related BRD4 protein).