Structure-based design used to map the entirety of the BET binding pocket and design best-in-class BET inhibitors

The BET (bromodomain and extra-terminal) proteins are four closely related bromodomain-containing proteins (BRD2, BRD3, BRD4, and BRDT) which constitute a subset of the larger family of 47 bromodomain-containing proteins. Bromodomains are acetyl-lysine binding pockets that target bromodomain-containing proteins to histones and thereby affect chromatin structure and function. The binding of BET protein bromodomains to chromatin regulates gene expression and small molecule inhibition of that binding produces selective effects on gene expression.

Of particular importance is the observation by Constellation scientists and others that MYC transcription can be suppressed using small molecule inhibitors of BET protein bromodomains (published in the Proceedings of the National Academy of Science). MYC is a master regulator of diverse cellular functions and has long been considered a compelling therapeutic target because of its role in many human malignancies. The regulation of MYC through BET inhibition was recognized by Nature Medicine as a 2011 Notable Achievement in Cancer Biology and by Science Signaling as a 2011 Biology Breakthrough of the Year. Small molecule inhibition of BET protein bromodomains also selectively suppresses other genes, such as Bcl-2, that have important roles in cancer, as well as some NF-kB-dependent genes that have roles in both cancer and inflammation.

Small molecule inhibition of BET bromodomains leads to selective killing of tumor cells across a broad range of hematologic malignancies and in subsets of solid tumors. Constellation has deployed its integrated drug discovery product engine, which includes proprietary screening strategies and structure-based drug design to identify novel, potent, and selective inhibitors of BET bromodomains. Constellation’s first BET inhibitor CPI-0610 is currently in three separate Phase 1 clinical studies.

Inhibition of BET bromodomain proteins by CPI-610

Inhibition of BET bromodomain proteins by CPI-0610 results in eviction of BET proteins from chromatin, reduces the expression of BET target genes and shows impressive tumor growth inhibition in an AML xenograft mouse model.