School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
Bioorg Chem. 2022 Nov;128:106069. doi: 10.1016/j.bioorg.2022.106069. Epub 2022 Jul 30.
RXRα, a unique and important nuclear receptor, plays a vital role in various biological and pathological pathways, including growth, differentiation, and apoptosis. We recently reported a transcription-independent function of RXRα in cancer cells in which RXRα is phosphorylated by Cdk1 at the onset of mitosis, resulting in its translocation to the centrosome, where the phosphorylated RXRα (p-RXRα) interacts with polo-like kinase 1 (PLK1) to promote centrosome maturation and mitotic progression. Significantly, we also identified that a small molecule XS-060 binds to RXRα and selectively inhibits the p-RXRα/PLK1 interaction to induce mitotic arrest and catastrophe in cancer cells. Here, we report our design, synthesis, and biological evaluation of a series of XS-060 analogs as RXRα-targeted anti-mitotic agents. Our results identified B10 as an improved anti-mitotic agent. B10 bound to RXRα (K = 3.04 ± 0.58 μM) and inhibited the growth of cervical cancer cells (HeLa, IC = 1.46 ± 0.10 μM) and hepatoma cells (HepG2, IC = 3.89 ± 0.45 μM and SK-hep-1, IC = 5.74 ± 0.50 μM) with low cytotoxicity to nonmalignant cells(LO2, IC > 50 μM). Furthermore, our mechanistic studies confirmed that B10 acted as an anticancer agent by inhibiting the p-RXRα/PLK1 pathway. These results provide a basis for further investigation and optimization of RXRα-targeted anti-mitotic molecules for cancer therapy.
RXRα 是一种独特而重要的核受体，在多种生物学和病理学途径中发挥着至关重要的作用，包括生长、分化和凋亡。我们最近报道了 RXRα 在癌细胞中的一种转录非依赖性功能，即在有丝分裂开始时，Cdk1 使 RXRα 磷酸化，导致其易位到中心体，磷酸化的 RXRα（p-RXRα）与 Polo 样激酶 1（PLK1）相互作用，促进中心体成熟和有丝分裂进程。重要的是，我们还发现一种小分子 XS-060 与 RXRα 结合并选择性抑制 p-RXRα/PLK1 相互作用，从而诱导癌细胞有丝分裂停滞和灾难。在这里，我们报告了一系列作为 RXRα 靶向抗有丝分裂剂的 XS-060 类似物的设计、合成和生物学评价。我们的结果确定 B10 为一种改良的抗有丝分裂剂。B10 与 RXRα 结合（K = 3.04 ± 0.58 μM）并抑制宫颈癌（HeLa，IC = 1.46 ± 0.10 μM）和肝癌细胞（HepG2，IC = 3.89 ± 0.45 μM 和 SK-hep-1，IC = 5.74 ± 0.50 μM）的生长，对非恶性细胞（LO2，IC > 50 μM）的细胞毒性低。此外，我们的机制研究证实，B10 通过抑制 p-RXRα/PLK1 通路发挥抗癌作用。这些结果为进一步研究和优化用于癌症治疗的 RXRα 靶向抗有丝分裂分子提供了基础。
