A pharmacologic approach to male contraception remains a longstanding challenge in medicine. Recent research from our laboratories has provided pharmacologic target validation for BRDT, a detemiinant of male fertility expressed in meiotic spemriatogonia. Using a chemical tool (JQ1) which targets the first bromodomain of BRDT, we have demonstrated the feasibility of small-molecule modulation of male fertility by targeting the male germ cell. Developed by the Bradner laboratory as an anti-cancer agent targeting BRD4, an evolutionarily related protein and emerging cancer dependency in hematologic malignancies, JQ1 lacks the selectivity and drug-like properties befitting a male contraceptive agent. We therefore propose research directed at the chemical optimization, biochemical characterization, mechanistic study and clinical translation of BRDT inhibitors. Using structure-function insights regarding the molecular recognition of human bromodomain proteins by natural ligands (acetyl-lysine containing peptides) and first-in-class bromodomain inhibitors developed by our laboratory, we propose to develop focused libraries of BRDT inhibitors using iterative cycles of synthesis and biochemical testing. Chemistry will proceed using three distinct chemical scaffolds, to avoid inter-dependency in this research. To support this research, we have developed robust, miniaturized biochemical assays for all BET bromodomain proteins. Beyond lead optimization, the homogeneous assay for BRDT will be further optimized for high-throughput screening within the Bradner laboratory and Institute of Chemistry and Cellular Biology, to maximize the opportunity for discovering selectivity-conferring chemotypes. Based on successful drug development projects completed by our group, we have organized a Project Management Plan, a Data Sharing Plan and a password-protected common cloud computing site, to assure that deliverables in chemistry and biology are met, and that data is provided to collaborating investigators in real-time. Pre-established criteria for the characteristics of a chemical probe for BRDT have been established, guiding our research. Lead compounds will be studied in a series of mechanistic studies of spermatogenesis in vivo, within the Matzuk laboratory. As the clinical objective of this research is to deliver a prototype therapeutic BRDT inhibitor, advanced lead compounds will be studied for phanmacologic properties in vitro and in vivo. It is expected that therapeutic agents will emerge from this research, prompting human clinical investigation.
The proposed research will convincingly advance basic scientific knowledge and is poised to contribute significantly to public health through the creation of novel male contraceptives that are potent and selective inhibitors of the male germ cell specific protein BRDT. Our data is the first to identify a drug that functions as a reversible contraceptive through its actions on the male germline. This research will also nucleate an interdisciplinary team of scientific investigators with complimentary expertise in chemistry, biochemistry, cell biology, developmental biology and fertility toward the common goal of developing a male contraceptive pill.
|McKeown, Michael R; Shaw, Daniel L; Fu, Harry et al. (2014) Biased multicomponent reactions to develop novel bromodomain inhibitors. J Med Chem 57:9019-27|
|Picaud, Sarah; Da Costa, David; Thanasopoulou, Angeliki et al. (2013) PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains. Cancer Res 73:3336-46|