Discovery of CECR2 Bromodomain Inhibitors with High Selectivities over BPTF Bromodomain

Comprehensive Summary Cat's eye syndrome chromosome candidate 2 bromodomain (CECR2 BRD) and Bromodomain PHD transcription factor bromodomain (BPTF BRD) are the same subfamily proteins, both of which are highly conserved in sequence and binding pockets. Challenges remain in the development of small molecules to inhibit one of the two bromodomains (BRDs), in view of each subtype may possess unique physiological and pathological functions. There is still a lack of effective selective inhibitors of CECR2 BRD, which makes it difficult to fully understand the pathogenesis of CECR2-BRD in diseases, especially cancers. Herein, we report our efforts to discover a series of highly selective CECR2 BRD inhibitors over BPTF BRD based on TP-248. Structure-based molecular optimization led to the discovery of DC-CEi-26, whose IC50 for CECR2 BRD was 96.7 +/- 14.9 nmol/L and selectivity was up to 590 x over BPTF BRD. DC-CEi-26 showed weak potencies for other classic BRDs in different subfamily, which may serve as a chemical probe for CECR2 BRD biological research.