Discovery of bipyridine amide derivatives targeting pRXR?-PLK1 interaction for anticancer therapy

Retinoid X receptor alpha (RXR alpha) is an important therapeutic target of cancer. Recently, small molecules (e.g., XS-060 and its derivatives), which can significantly induce RXR alpha-dependent mitotic arrest by inhibiting pRXR alpha-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 RXR alpha. The most active compound, bipyridine amide B9 (BPA-B9), showed better activity than XS-060, with excellent RXR alpha-binding affinity (KD = 39.29 +/- 1.12 nM) and anti -proliferative activity against MDA-MB-231 (IC50 = 16 nM, SI > 3). Besides, a docking study revealed a proper fitting of BPA-B9 into the coactivator binding site of RXR alpha, rationalizing its potent antagonistic effect on RXR alpha transactivation. Further, the mechanism studies revealed that the anticancer activity of BPA-B9 was dependent on its cellular RXR alpha-targeted mechanism, such as inhibiting pRXR alpha-PLK1 interaction and inducing RXR alpha-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 RXR alpha ligand BPA-B9 targeting the pRXR alpha-PLK1 interaction, with great potential as a promising anticancer drug candidate for further development.