A NOVEL ENSEMBLE APPROACH TO PROVIDING SMALL MOLECULE SUPPORT FOR VALIDATION OF CELLULAR TARGETS CON

Ziyan Zhao, Rahul Rajagopalan and Adam Zweifach

Dept of Molecular and Cell Biology, University of Connecticut, Connecticut, Storrs, United States

Abstract

Cancer drug discovery programs fail too often. One cause may be weak small molecule support at the target validation stage, since the tool compounds available at that point are not optimized and often have multiple effects. Aserobic glycolysis- the Warburg effect- has recently reemerged as a potential cancer target attracting considerable interest, but small molecule support for blocking glycolysis constituting an effective antiproliferative strategy is not strong. We developed a new assay based on expression of an intramolecular FRET sensor for ATP in K562 cells, and used it to screen a National Cancer Institute compound cellection for metabolically-active small molecules. We identified 10 compounds that inhibit glycolysis, and 7 that inhibit ATP produced via oxidative phosphorylation in the absence of glucose and glutamine. The oxidative phosphorylation inhibitors were no more effective at blocking proliferation than the overall compound set, while all of the glycolysis inhibitors were in the top third of most effective antiproliferative compounds. Knowing the growth-inhibiting properties of the library, the odds of this occurring by chance can be estimated and are vanishingly small. Our results point to a approach to providing small molecule support for targets that could be applied prospectively prior to large scale screening. Adopting this approach could help reduce the failure rate of drug development efforts.

Keywords: Cancer drug discovery, metabolism, target validation, screening.