Design, synthesis and biological evaluation of potent and selective pyruvate carboxylase (PC) inhibitors for studying cancer cell metabolism

About This Grant

Project Summary Cancer represents a group of diseases that has had a profound impact on human society, not only in terms of health care but also by imposing significant financial strain on those directly or indirectly affected. To address this growing health crisis, there remains an urgent need for education, early diagnosis, and continued research into cancer prevention. Currently, the development of targeted cancer therapies is hampered by an incomplete understanding of the mechanisms that allow cancer cells to switch between metabolic pathways in response to environmental conditions or treatments. Lying at the crossroads of central metabolism is the enzyme pyruvate carboxylase (PC), which impacts both anabolic and catabolic processes. PC converts pyruvate to oxaloacetate which plays a crucial role in cancer metabolism by replenishing the TCA cycle intermediates that allow cancer cells to sustain their energy production and biosynthesis under nutrient-limiting conditions. While many studies have linked aberrant PC expression to cancer, there have been only limited efforts to develop pharmacological modulators to study the role of PC in cancer cell metabolism. Employing a structure-based drug discovery approach, this project seeks to generate potent and selective small molecule inhibitors that can serve as a valuable new toolkit for studying cancer cell metabolism and that may ultimately facilitate the development of new chemotherapeutic agents against cancer. PC inhibitors will be developed and characterized using two independent but highly complementary approaches: (1) An extended structure-activity relationship will be developed on an existing scaffold that displays low μM affinity against PC; (2) In parallel, two weak allosteric PC inhibitors, aspartate and glutamate, will be chemically exploited to generate a series of molecules with increased potency and selectivity for PC. These compounds will be characterized using multiple in-vitro screening assays. The most promising compounds from both approaches will be characterized using a suite of kinetic, cellular and structural studies. This project will bring together undergraduate students in an inter-disciplinary research team that offers exposure to medicinal chemistry, protein biochemistry, cell biology, and structural biology. .