Journal of Medicinal Chemistry
Journal of Medicinal Chemistry
5 years ago

Structure-Based Design of Highly Selective Inhibitors of the CREB Binding Protein Bromodomain

Structure-Based Design of Highly Selective Inhibitors of the CREB Binding Protein Bromodomain
Paul Bonin, Lyn H. Jones, Paul E. Brennan, Shenping Liu, Andrew C. Flick, R. Aldrin Denny, Jotham Coe, Parag Sahasrabudhe, Jonathan Langille, Arindrajit Basak, Mathew Pletcher, Duncan A. Hay, Eugene L. Piatnitski Chekler, Ingrid Stock
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).

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.6b01839

DOI: 10.1021/acs.jmedchem.6b01839

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