credit Graham Garnett
We use organic synthesis and a variety of bioanalytical techniques to design, make, and study molecules that bind their targets in a biological setting. We also collaborate closely with several biochemistry and cancer-research laboratories to translate these discoveries into practical advances in the understanding and treatment of disease. Overviews of two areas in which we work are given below. Check out our recent papers for detailed information on our most recent research directions.
chemical biology and medicinal chemistry of epigenetic reader proteins
Post-translational methylations of amino acids are part of the so-called “Histone Code” of epigenetic gene regulation mechanisms. Certain lysine and arginine residues can be methylated by methyltransferase enzymes in reactions that are highly target and site specific. Methylation pathways control gene expression and increasing evidence shows that 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 for aggressive cancers of the prostate, breast, 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 subsequent structure-guided optimizations. Inhibiting these proteins allows for a greater understanding of the structure-activity relationships for protein binding in this family. In one example (J. Med. Chem. 2014), we created the first inhibitors of any chromodomain (a family of methyllysine readers), inhibiting CBX7. 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, Vancouver General Hospital, and in multiple international labs who use our chemical probes against those and other proteins to uncover the reader proteins’ roles in aggressive cancers and test their potential as new therapeutic targets.
supramolecular capture agents / new bioanalytical methods
We are generally interested in creating host-guest molecular recognition systems that can operate in pure water and in real biological fluids. These systems can be programmed to bind specifically to a variety of analytes, and much of our work has targeted post-translationally modified peptides and proteins (ChemBioChem 2010, Chem. Sci. 2012, JACS 2012, Org. Lett. 2012, Acc. Chem. Res. 2013, Org. Biomol. Chem. 2013, Bioorg Med. Chem. 2013, Biochem J. 2014, J. Biol. Chem. 2015, Chem. Sci. 2015). We have also targeted a small-molecule cancer biomarker (Analyst, 2014). These recognition systems are then interfaced with sensitive detection methods including fluorescence (JACS 2012), luminescence, and nanomaterial-driven surface enhanced Raman spectroscopy. One of the guiding motivations for our work in this area is that affinity tools that are pure, homogenous chemical agents will have reproducibility and stability that is better than that of notoriously finicky antibody-based reagents (Anal. Chem. 2016). Funded projects that fall generally in this area include: creating new enzyme assays that operate via a novel supramolecular mechanism, creating proteomics tools for studying trimethyllysine marks, the development of new methods to discover supramolecular hosts by chemical evolution and massive diversity, developing new agents that target every known post-translational modification, and early cancer detection by simple urinalysis. We're even doing applied science that aims to improve brewing by using our new bioanalytical methods to study yeast fermentation biology.
-Prostate Cancer Canada/Movember
-Michael Smith Foundation for Health Research
-Canadian Institutes of Health Research (New Investigator Award)
-Canadian Breast Cancer Foundation (BC/Yukon)