Development of small molecule inhibitors of ULK1

National Center For Advancing Translational Sciences

Investigators

Abstract

Several types of cancers, like pancreatic cancer, have been shown to be particularly dependent on autophagy for growth and survival. This project aims to develop potent, selective and bioavailable small molecule inhibitors of ULK1, an enzyme that initiates autophagy, to enable translation of the hypothesis: autophagy inhibition via ULK1 is a valid therapeutic approach for pancreatic cancer. During this period, the collaborative team performed hit-to-lead optimization and synthesized potent, stable leads with desirable biophysical properties amendable for in vivo studies. However, examination of the kinase selectivity of these leads revealed that they can potently inhibit a number of other kinases as well, which obscure the analysis of cell-based efficacy evaluation. Analogs specifically designed for selectivity based on docking models have been synthesized and their selectivity will be evaluated.