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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).

Original publication

DOI

10.1021/acs.jmedchem.6b01839

Type

Journal article

Journal

J Med Chem

Publication Date

13/07/2017

Volume

60

Pages

5349 - 5363

Keywords

CREB-Binding Protein, Chemistry, Pharmaceutical, Dose-Response Relationship, Drug, Drug Design, E1A-Associated p300 Protein, Humans, Molecular Structure, Morpholines, Structure-Activity Relationship