Screening And Identification Of New Generation Glucose Transporter Inhibitors As Anticancer Therapeutics

Abstract Cancer is a top killer second only to cardiovascular diseases. Cellular metabolic reprogramming and altered energetics are key features of cancer. Opportunistic uptake of extracellular nutrients has recently been named as an emerging hallmark of cancer metabolism. Glucose is a key nutrient taken in by cancer cells for satisfying their high energy and biosynthesis needs. Drastic upregulation of glucose uptake and glycolytic activity, a phenomenon called the Warburg effect, is prevalent in cancers. Cancer cells overexpress specific glucose transporters (Gluts), particularly Glut1, on cell membranes for taking in glucose via facilitated diffusion. Considering the addiction of cancer cells for glucose and their sensitivity and vulnerability to changes in glucose supply, Gluts, especially Glut1, have been recognized as an attractive anticancer target. We previously reported the identification of first generation lead Glut1 inhibitor WZB117 (1). WZB117 treatment of human nonsmall cell lung cancer (NSCLC) A549 cells resulted in inhibition of glucose uptake, glycolysis and induction of apoptosis and necrosis. In addition, WZB-117 reduced tumor growth by ~70% in an A549 tumor mouse model. WZB117 inhibit cell growth of 7 cancer cell lines in 4 cancer types with IC50 values lower than 10 μM. Through a structure activity relationship (SAR) study of WZB117, a second generation lead, DRB18, has been identified. DRB-18 is much more stable and 5 to 10 times more potent than WZB117 in inhibiting growth and proliferation in about 90% of the 60 different cancer cell lines in 9 major cancer types as revealed in NCI-60 screenings. And its IC50s in many cancer cell lines are in the high nM range. In this study, we also report new compounds screening results for the objective of identifying novel compounds with higher glucose transport-inhibitory and cancer cell growth-inhibitory activities using nonsmall cell lung cancer cell lines as models. References: 1. Liu, Y., Cao, Y., Zhang, W., Bergmeier, S., Qian, Y., Akbar, H., Colvin, R., Ding, J., Tong, L., Wu, S. and Hines, J., 2012. A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Molecular cancer therapeutics, 11(8):1672-1682. Citation Format: Yanrong Qian, Pratik Shriwas, Xuan Wang, Dennis Roberts, Emma Kessler, Stephen Bergmeier, Xiaozhuo Chen. Screening and identification of new generation glucose transporter inhibitors as anticancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1157. doi:10.1158/1538-7445.AM2017-1157