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Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
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Design, synthesis and biological evaluation of acyl hydrazones-based derivatives as RXRα-targeted anti-mitotic agents

Qiqiang Wang1, Xuhuang Tu1, Xin Wang1

  • 1School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.

Bioorganic Chemistry
|August 14, 2022
PubMed

Insights

Researchers developed B10, a new anti-mitotic drug targeting the phosphorylated RXRα/PLK1 pathway. This molecule effectively inhibits cancer cell growth with low toxicity to normal cells, offering a promising new avenue for cancer therapy.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Medicinal Chemistry

Background:

  • Retinoid X receptor alpha (RXRα) is crucial in biological pathways and cancer.
  • A transcription-independent function of RXRα involves its phosphorylation and centrosome interaction during mitosis.
  • This interaction with polo-like kinase 1 (PLK1) promotes cancer cell division.

Purpose of the Study:

  • To design, synthesize, and evaluate novel RXRα-targeted anti-mitotic agents.
  • To identify improved analogs of the small molecule XS-060.
  • To explore new therapeutic strategies for cancer treatment by targeting the p-RXRα/PLK1 pathway.

Main Methods:

  • Synthesis and biological evaluation of XS-060 analogs.
  • Binding assays to determine affinity for RXRα.
  • Cell viability assays on cancer and nonmalignant cell lines.
  • Mechanistic studies to confirm pathway inhibition.

Main Results:

  • Identified B10 as a potent anti-mitotic agent with strong binding to RXRα (Kd = 3.04 ± 0.58 μM).
  • B10 significantly inhibited growth of cervical cancer (HeLa, IC50 = 1.46 ± 0.10 μM) and hepatoma cells (HepG2, IC50 = 3.89 ± 0.45 μM; SK-hep-1, IC50 = 5.74 ± 0.50 μM).
  • B10 demonstrated low cytotoxicity to nonmalignant LO2 cells (IC50 > 50 μM) and confirmed inhibition of the p-RXRα/PLK1 pathway.

Conclusions:

  • B10 is an effective RXRα-targeted anti-mitotic agent with a favorable selectivity profile.
  • Inhibition of the p-RXRα/PLK1 interaction represents a viable strategy for cancer therapy.
  • Further development of B10 and similar molecules holds promise for future cancer treatments.
Keywords:
Acyl hydrazonesMitosisNuclear ReceptorsPLK1RXRα

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