Epigenetic drug development
Lysine and arginine methylation pathways control gene expression, and misregulation of these pathways leads to disease. In most cases, methylation turns on a protein-protein interaction with a “reader” protein. We are interested both in learning about reader protein chemical biology, and in achieving the chemical disruption of reader proteins as a novel route to epigenetic therapies. Our targets are aggressive cancers of the prostate, breast, liver, ovary, blood, and other tissues.
In one family of projects, our lab makes inhibitors of the reader proteins that bind to post-translational modifications in our bodies. Polycomb group proteins — proteins that are upregulated in certain aggressive stem-like cancers — are one family of targets for our efforts. We develop new protein-binding assays, and use them to develop and optimize reader protein inhibitors using many methods, including peptide-driven approaches, high-throughput screening, and structure-guided optimizations. In one example (J. Med. Chem. 2014), we created the first inhibitors of any chromodomain (a family of methyllysine readers), inhibiting CBX7. In another typical example we developed SAR that allowed us to hop to another family member, CBX6 (ACS Med. Chem. Lett. 2016). We are working with collaborators at the BC Cancer Agency and Centre for Drug Research and Development (www.cdrd.ca), and in multiple international labs who bring their unique techniques (e.g. DNA encoded chemistry) to our efforts to uncover the reader proteins’ roles in aggressive cancers and test their potential as new therapeutic targets.