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.
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.
Eur J Med Chem. 2023 Jun 5;254:115341. doi: 10.1016/j.ejmech.2023.115341. Epub 2023 Apr 6.
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 (K = 39.29 ± 1.12 nM) and anti-proliferative activity against MDA-MB-231 (IC = 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.
视黄醇 X 受体α（RXRα）是癌症的一个重要治疗靶点。最近，一些小分子（如 XS-060 及其衍生物）通过抑制 pRXRα-PLK1 相互作用，显著诱导 RXRα 依赖性有丝分裂阻滞，已被证明是优秀的抗癌剂。为了进一步获得具有优异生物活性和类药性的新型 RXR 靶向抗有丝分裂剂，我们以 XS-060 为先导化合物，合成了两个新系列的双吡啶酰胺衍生物。在报告基因检测中，大多数合成化合物对 RXRα 表现出拮抗活性。最活跃的化合物双吡啶酰胺 B9（BPA-B9）比 XS-060 表现出更好的活性，具有更好的 RXRα 结合亲和力（K = 39.29 ± 1.12 nM）和对 MDA-MB-231 的抗增殖活性（IC = 16 nM，SI > 3）。此外，对接研究表明 BPA-B9 能够适当的进入到 RXRα 的共激活剂结合位点，合理地解释了其对 RXRα 反式激活的强烈拮抗作用。进一步的机制研究表明，BPA-B9 的抗癌活性依赖于其细胞 RXRα 靶向作用机制，如抑制 pRXRα-PLK1 相互作用和诱导 RXRα 依赖性有丝分裂阻滞。此外，BPA-B9 显示出比先导化合物 XS-060 更好的药代动力学性质。此外，动物实验表明，BPA-B9 在体内具有显著的抗癌疗效，且没有明显的副作用。综上所述，我们的研究揭示了一种新型的 RXRα 配体 BPA-B9，它可以靶向 pRXRα-PLK1 相互作用，具有作为一种很有前途的抗癌药物候选物进一步开发的潜力。
