Abstract

Retinoid X receptor alpha (RXRα) is an important therapeutic target of cancer. Recently, small molecules ( e.g., XS-060 and its derivatives), which can significantly induce RXRα-dependent mitotic arrest by inhibiting p RXRα-PLK1 interaction, have been demonstrated as excellent anticancer agents . To further obtain novel RXR-targeted antimitotic agents with excellent bioactivity and drug-like properties, we herein synthesized two new series of bipyridine amide derivatives with XS-060 as the lead compound. In the reporter gene assay, most synthesized compounds showed antagonistic activity against RXRα. The most active compound, bipyridine amide B9 (BPA-B9) , showed better activity than XS-060 , with excellent RXRα-binding affinity ( K D  = 39.29 ± 1.12 nM) and anti-proliferative activity against MDA-MB-231 (IC 50  = 16 nM, SI > 3). Besides, a docking study revealed a proper fitting of BPA-B9 into the coactivator binding site of RXRα, rationalizing its potent antagonistic effect on RXRα transactivation . Further, the mechanism studies revealed that the anticancer activity of BPA-B9 was dependent on its cellular RXRα-targeted mechanism, such as inhibiting p RXRα-PLK1 interaction and inducing RXRα-dependent mitotic arrest. Besides, BPA-B9 displayed better pharmacokinetics than the lead XS-060. Further, animal assays indicated BPA-B9 had significant anticancer efficacy in vivo with no considerable side effects. Together, our study reveals a novel RXRα ligand BPA-B9 targeting the p RXRα-PLK1 interaction, with great potential as a promising anticancer drug candidate for further development.