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Bromodomains are gaining increasing interest as drug targets. Commercially sourced and de novo synthesized substituted [1,2,4]triazolo[4,3-a]phthalazines are potent inhibitors of both the BET bromodomains such as BRD4 as well as bromodomains outside the BET family such as BRD9, CECR2, and CREBBP. This new series of compounds is the first example of submicromolar inhibitors of bromodomains outside the BET subfamily. Representative compounds are active in cells exhibiting potent cellular inhibition activity in a FRAP model of CREBBP and chromatin association. The compounds described are valuable starting points for discovery of selective bromodomain inhibitors and inhibitors with mixed bromodomain pharmacology.

Original publication

DOI

10.1021/jm401568s

Type

Journal article

Journal

Journal of Medicinal Chemistry

Publication Date

01/2014

Volume

57

Pages

462 - 476

Addresses

Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.

Keywords

Cell Line, Tumor, Humans, Triazoles, Phthalazines, Proteins, Nuclear Proteins, Transcription Factors, Crystallography, X-Ray, Chromatin Assembly and Disassembly, Protein Structure, Tertiary, Structure-Activity Relationship, CREB-Binding Protein, Molecular Docking Simulation