A Potent and Selective ULK1 Inhibitor Suppresses Autophagy and Sensitizes Cancer Cells to Nutrient Stress

In response to stress, Cancer cells generate nutrients and energy through a cellular recycling process called Autophagy, which can promote survival and tumor progression. Accordingly, Autophagy inhibition has emerged as a potential Cancer treatment strategy. Inhibitors targeting ULK1, an essential and early Autophagy regulator, have provided proof of concept for targeting this kinase to inhibit autophagy; however, these are limited individually in their potency, selectivity, or cellular activity. In this study, we report two small molecule ULK1 inhibitors, ULK-100 and ULK-101, and establish superior potency and selectivity over a noteworthy published inhibitor. Moreover, we show that ULK-101 suppresses Autophagy induction and autophagic flux in response to different stimuli. Finally, we use ULK-101 to demonstrate that ULK1 inhibition sensitizes KRAS mutant lung Cancer cells to nutrient stress. ULK-101 represents a powerful molecular tool to study the role of Autophagy in Cancer cells and to evaluate the therapeutic potential of Autophagy inhibition.