Novel, Cellular Active Inhibitors Of G6pd, A Key Mediator Of Ros-Induced Cellular Stress

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in the pentose phosphate pathway (PPP) and catalyses the oxidation of glucose-6-phosphate to glucono-δ-lactone-6-phosphate with the concomitant production of NADPH. Alongside an important role in the production of biosynthetic precursors such as ribonucleotides, this pathway is a major cellular source of NADPH. As such, the pathway plays a critical role in both the biosynthesis of fatty acids & cholesterol biosynthesis (thus supporting cell division) and maintaining glutathione in its reduced state (GSH), the latter ameliorating cellular stress arising from reactive oxygen species (ROS). Given these key roles, modulation of the pathway has potential therapeutic application, and inhibition of G6PD is an attractive target, particularly in combination with standard of care radiotherapy or cytotoxic drugs which can increase ROS. We have developed a series of novel steroid G6PD inhibitors which, in our hands, modulate flux through the PPP and increase ROS-induced stress in cells. This disclosure will describe some of our results in this area. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1139. doi:1538-7445.AM2012-1139