Synthesis and in Vitro Anticancer Activity of the First Class of Dual Inhibitors of REV-ERBβ and Autophagy

Autophagy
inhibition is emerging as a promising anticancer strategy. We recently
reported that the circadian nuclear receptor REV-ERBβ plays
an unexpected role in sustaining cancer cell survival when the autophagy
flux is compromised. We also identified 4-[[[1-(2-fluorophenyl)­cyclopentyl]­amino]­methyl]-2-[(4-methylpiperazin-1-yl)­methyl]­phenol, 1 (ARN5187), as a novel dual inhibitor of REV-ERBβ and
autophagy. 1 had improved cytotoxicity against BT-474
breast cancer cells compared to chloroquine, a clinically relevant
autophagy inhibitor. Here, we present the results of structure–activity
studies, based around 1, that disclose the first class
of dual inhibitors of REV-ERBβ and autophagy. This study led
to identification of 18 and 28, which were
more effective REV-ERBβ antagonists than 1 and
were more cytotoxic to BT-474. The combination of optimal chemical
and structural moieties of these analogs generated 30, which elicited 15-fold greater REV-ERBβ inhibitory and cytotoxic
activities compared to 1. Furthermore, 30 induced death in a panel of tumor cell lines at doses 5–50
times lower than an equitoxic amount of chloroquine but did not affect
the viability of normal mammary epithelial cells.