更新于：2024-11-01

PLK1 x RXRA

更新于：2024-11-01

基本信息

关联

项与 PLK1 x RXRA 相关的药物

BPA-B9

靶点

PLK1 x RXRA

作用机制

PLK1抑制剂 [+1]

在研机构

厦门大学

原研机构

厦门大学

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PLK1 x RXRA 相关的临床结果

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100 项与 PLK1 x RXRA 相关的转化医学

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0 项与 PLK1 x RXRA 相关的专利（医药）

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项与 PLK1 x RXRA 相关的文献（医药）

2023-06-01·European Journal of Medicinal Chemistry

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

Article

作者: Fang, Meijuan ; He, Fengming ; Tang, Ziqing ; Zhao, Taige ; Chen, Jun ; Zhong, Yijing ; Wu, Zhen ; Wang, Susu ; Qiu, Yingkun

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_D = 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.

2020-12-01·Developmental Cell1区 · 生物学

Centrosomal Localization of RXRα Promotes PLK1 Activation and Mitotic Progression and Constitutes a Tumor Vulnerability

1区 · 生物学

Article

作者: Tu, Xuhuang ; Xie, Chengrong ; Ye, Xiaohong ; Xiao, Zhijian ; Su, Ying ; Xu, Lin ; Xia, Ji ; Xie, Guobin ; Wang, Xin ; Zhang, Xiaoli ; Chen, Ziwen ; Zhou, Yuqi ; Du, Mingxuan ; Wang, Qiqiang ; Chi, Xiaoqin ; Zhou, Yunxia ; Li, Zongxi ; Yin, Zhenyu ; Sheng, Luoyan ; Zhang, Xiaowei ; Zhou, Hu ; Zeng, Zhiping ; Xu, Yang ; Zhang, Xiao-Kun

Retinoid X receptor alpha (RXRα), a nuclear receptor of transcription factor, controls various physiological and pathological pathways including cellular growth, proliferation, differentiation, and apoptosis. Here, we report that RXRα is phosphorylated at its N-terminal A/B domain by cyclin-dependent kinase 1 (Cdk1) at the onset of mitosis, triggering its translocation to the centrosome, where phosphorylated-RXRα (p-RXRα) interacts with polo-like kinase 1 (PLK1) through its N-terminal A/B domain by a unique mechanism. The interaction promotes PLK1 activation, centrosome maturation, and mitotic progression. Levels of p-RXRα are abnormally elevated in cancer cell lines, during carcinogenesis in animals, and in clinical tumor tissues. An RXRα ligand XS060, which specifically inhibits p-RXRα/PLK1 interaction but not RXRα heterodimerization, promotes mitotic arrest and catastrophe in a tumor-specific manner. These findings unravel a transcription-independent action of RXRα at the centrosome during mitosis and identify p-RXRα as a tumor-specific vulnerability for developing mitotic drugs with improved therapeutic index.

2020-12-01·Developmental Cell1区 · 生物学

Moonlighting at the Centrosome: RXRα Turns to Plk1

1区 · 生物学

Article

作者: Elowe, Sabine ; Dos Santos, Alexsandro

One of the hardest working mitotic proteins, Polo-like kinase 1 (PLK1), functions at mitotic entry, cytokinesis, and many steps in between. In this issue, Xie et al. (2020) describe a centrosome-specific interaction between PLK1 and Retinoid X Receptor-α and they test selective inhibition of this interaction as an anti-mitotic cancer therapy.