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 a Phase 1 clinical study.
Lysine methyltransferases and demethylases have been identified as transcriptional co-regulators by either preserving particular chromatin methylation states or by controlling placement and removal of histone lysine methylation marks to promote dynamic changes in gene expression. EZH2 is an important histone lysine methyltransferase that works cooperatively as part of a multi-subunit complex known as PRC2. EZH2 is responsible for methylating a key residue (H3K27) on histone tails.
EZH2 is over-expressed in many solid tumors and hematologic malignancies, where expression levels strongly correlate with late stage disease poor prognosis. EZH2 is also activated by mutation in some diffuse large B-cell and follicular lymphomas. Further, functional data implicate EZH2 in tumor initiation and progression, stem cell self-renewal, migration and angiogenesis.
Constellation has leveraged its product engine to identify tractable series of small molecule inhibitors of EZH2. Central to its success in the identification of genuine EZH2 inhibitors is Constellation’s ability to flexibly utilize a diverse array of substrates (from simple peptides to complex chemically-modified and reconstituted oligonucleosomes) in its biochemical assays. Additionally, Constellation has developed proprietary assay technologies to assess the physical binding of small molecule inhibitors to EZH2 and to characterize their mechanism of action on chromatin in vitro and in vivo. Novel, potent, and selective inhibitors of EZH2 are currently being tested in preclinical studies.
Constellation is pursuing discovery programs against multiple targets in the reader, writer, and eraser classes of epigenetic proteins. Constellation has developed proprietary tools and assays to biologically validate the function of the members of these target classes. In parallel, Constellation is employing its integrated expertise in biochemistry, biophysics, medicinal chemistry, pharmacology and translational medicine to advance these discovery programs to the clinic. In January 2012 Constellation joined Genentech in an exclusive strategic alliance to broadly explore and validate additional targets in epigenetics and to discover and develop novel small molecule therapeutics against these important targets.