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Cancer; inflammation

BET bromodomain proteins; CREB binding protein (CREBBP; CBP); E1A binding protein p300 (EP300; p300)

In vitro studies have identified 5-isoxazolyl-benzimidazole inhibitors of non-BET bromodomains in CBP and p300 that could serve as scaffolds for new cancer compounds. A 3,5-dimethylisoxazole bromodomain inhibitor fragment was used as a scaffold to design an optimized 5-isoxazolyl-benzimidazole that bound the CBP and p300 bromodomains with nanomolar affinity and
40-fold selectivity over the BRD4 BET bromodomain. In cell culture, the 5-isoxazolyl-benzimidazole inhibited CBP-mediated p53 activity and showed low cytotoxicity. Ongoing work includes profiling the activity of the compound, SGC-CBP30, in cells from patients with autoimmune diseases and developing new selective inhibitors.
At least four companies have BET bromodomain inhibitors in Phase I testing to treat various cancers.
SGC-CBP30 is a molecular probe available for purchase from chemical suppliers.

SciBX 7(29); doi:10.1038/scibx.2014.875
Published online July 31, 2014

Unpatented; licensing status not applicable

Hay, D.A. et al. J. Am. Chem. Soc.; published online June 19, 2014;
Contact: Paul E. Brennan, University of Oxford, Oxford, U.K.