Discovery of Autophagy-Inducing Chloroquine Analogs with Potent Anticancer Activity in Breast Cancer Cells

Abstract

Targeting autophagy in cancer has emerged as a promising strategy for drug discovery. Autophagy is a conserved process required for the degradation and recycling of damaged organelles and proteins. Dysregulation of autophagy has been implicated in many diseases including cancer. In breast cancer, studies have demonstrated that activated autophagy promotes cell survival and therapeutic resistance. Chloroquine (CQ), an antimalarial and anti-inflammatory agent, has emerged as a potentialanticancer agent due to its autophagy inhibitory activity; however, it lacks specificity and potency. In this study, we report the synthesis and evaluation of several CQ analogs.Interestingly, the most potent compounds identified 5 and 6, induced autophagy, as they enhanced the accumulation of LC3B-II and induced p62 protein degradation. Cotreatment of MDA-MB-231 cells with compound 5 and bafilomycin A1, an autophagy inhibitor, resulted in blocking apoptosis induction concomitant with partial rescue of cell viability, suggesting induction of autophagy-dependent apoptosis.