Design, synthesis and biological evaluation of acyl hydrazones-based derivatives as RXRα-targeted anti-mitotic agents

Abstract

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_d = 3.04 ± 0.58 μM) and inhibited the growth of cervical cancer cells (HeLa, IC₅₀ = 1.46 ± 0.10 μM) and hepatoma cells (HepG2, IC₅₀ = 3.89 ± 0.45 μM and SK-hep-1, IC₅₀ = 5.74 ± 0.50 μM) with low cytotoxicity to nonmalignant cells(LO2, IC₅₀ > 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.

Keywords: Acyl hydrazones; Mitosis; Nuclear Receptors; PLK1; RXRα.