Screening For Anti-cancer Drugs Targeting Retinoid X Receptor-alpha

Retinoid X receptor alpha(RXRa),a member of the nuclear receptor superfamily,acts as a ligand-dependent transcription factor.RXRa is implicated in the regulation of cell growth,differentiation,apoptosis,metabolism and various physiological and pathological processes.The abnormal expression,localization,or function of RXRa is associated with the development of many cancers and diseases in humans,and many small molecule ligands of RXRa have shown promising therapeutic effects against cancer and diseases,amking RXRa an important target for drug development.Cytokinesis is the final stage of the cell cycle and is the physical separation of daughter cells after chromosome segregation during mitosis.Aberrant cytokinesis can cause the unstable genome of cells and cause cell death or carcinogenesis.At the time of cytokinesis,the intercellular bridge is formed between daughter cells.Evidence is emerging to show that proteins factors involved in the regulation or execution of the division are locate in this structure to modulate cell division.However,the underlying molecular mechanism remains obscure.Recently,our laboratory discovered a novel critical role of RXRa during cytokinesis,in which RXRa upon Cdkl phosphorylation acts to regulate cytokinetic abscission by interacting at the intercellular bridge with PLK1(Polo-like kinase 1),a master regulator of mitosis and cytokinesis.As RXRa is oftern hyperphosphorylated in tumor cells,we hypothesized that phosphorylated RXRα acts via our newly discovered pathway to promote cancer cell proliferation.Thus,the aim of this project was to identify new RXRa modulators that inhibit RXRa-mediated cytokinesis and tumor cell proliferation.We established an in vitro model syetem for screening compounds that bind RXRa and inhibit its interaction with PLK1.Our results identified XS060 that binds RXRa with micromolar affinity and importantly the binding inhibits RXRa interaction with PLK1.In cell-based exepriments,XS060 treatment effectively caused abnormal localization of PLK1 at the intercellular bridge,delayed the abscission process,caused cell cycle arrested in M phase,and induced apoptosis in a variety of tumor cell lines.We further modified the structure of the XS060 and synthesized a series of derivatives.One derivative was identified,which showed better effects than XS060 in inducing M-phase cycle arrest activity and inhibiting RXRa/PLK1 interaction.Thus,XS060 and analogs have the potential to be developed into a novel antineoplastic agent targeting RXRα.They also represent important tools in dissecting our newly discovery RXRa-mediated cytokinesis pathway.