Identification of a Dual Autophagy and REV-ERB Inhibitor with <i>in Vivo</i> Anticancer Efficacy

The autophagy process
appears as a promising target for anticancer
interventions. Chloroquine (CQ) and its derivative hydroxychloroquine
(HCQ) are the only FDA-approved autophagy flux inhibitors. Although
diverse anticancer clinical trials are providing encouraging results,
several limitations associated with the need of high dosage and long-term
administration of these autophagy inhibitors are also emerging. We
showed that the inhibition of REV-ERB, a nuclear receptor regulating
circadian rhythm and metabolism, enhances CQ-mediated cancer cell
death and identified a class of dual inhibitors of autophagy and REV-ERB
displaying an in vitro anticancer activity against
diverse tumor cells greatly higher than CQ. Herein, we describe our
lead optimization strategy that led to the identification of compound 24 as a dual autophagy and REV-ERB inhibitor, showing improved
potency in blocking autophagy, enhanced toxicity against cancer cells,
optimal drug-like properties, and efficacy in a mouse xenograft model
of melanoma as a single anticancer agent.