Grant: Master's Award: Canada Graduate Scholarships

Misregulation of changes in gene expression and function, and abnormal silencing of genes occurs in cancer, affecting tumor growth and the spread of the disease. Chromobox 7 (CBX7) is a polycomb group protein crucial in regulating cellular processes. Gene silencing by CBX7, represses tumor suppressors, leading to cancer progression. CBX7 has increasingly been strongly linked to cancer progression, particularly in prostate cancer and the incurable form, castrate resistant prostate cancer. Small molecule inhibitors of the CBX7 chromodomain will selectively target the portion of the protein that is required for pro-growth phenotypes in cancer, and shed light onto new theraputic tools necessary to help combat the disease. Aims of the project are to a) make potent macrocyclic inhibitors of CBX7 that will interact with the molecules chromodomain b) test and optimize them for selectivity and potency among protein paralogs c) test their ability to kill prostate cancer cells in vitro myself as a lead-in to preclinical studies in mice, and to establish the mechanisms of this pathway in prostate cancer by examining their effects on genome-wide expression profiles in collaboration with the Collins group, Vancouver Prostate Centre. Progress of the project will be measured by the number of drug candidates made, their achievement of inhibition of CBX7, and by their efficacy in human prostate cancer cell lines as tested by the Collins group. The research proposed is a new direction, but will contribute to the large and growing field of studying the role of polycomb proteins in aggressive cancers. We expect the synthesized cyclic molecules to inhibit CBX7, demonstrate strong selectivity and potency, as well as to have a positive effect on inhibiting proliferation in human prostate cancer cell lines.