1. Academic Validation
  2. Discovery of bipyridine amide derivatives targeting pRXRα-PLK1 interaction for anticancer therapy

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

  • Eur J Med Chem. 2023 Apr 6;254:115341. doi: 10.1016/j.ejmech.2023.115341.
Jun Chen 1 Taige Zhao 1 Fengming He 1 Yijing Zhong 1 Susu Wang 1 Ziqing Tang 1 Yingkun Qiu 1 Zhen Wu 2 Meijuan Fang 3
Affiliations

Affiliations

  • 1 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Science, Xiamen University, Xiamen, 361102, China.
  • 2 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Science, Xiamen University, Xiamen, 361102, China. Electronic address: wuzhen@wmu.edu.cn.
  • 3 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Science, Xiamen University, Xiamen, 361102, China. Electronic address: fangmj@xmu.edu.cn.
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 pRXRα-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 (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 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 pRXRα-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 pRXRα-PLK1 interaction, with great potential as a promising Anticancer drug candidate for further development.

Keywords

Antagonist; Anticancer activity; Mitotic arrest; Protein-protein interaction; RXRα.

Figures
Products