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Real-Time Monitoring of Aurora kinase A Activation using Conformational FRET Biosensors in Live Cells
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Optimization and biological evaluation of nicotinamide derivatives as Aurora kinase inhibitors

Baohui Qi1, Xingwei Xu1, Ying Yang1

  • 1Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, Guangdong Province, China.

Bioorganic & Medicinal Chemistry
|July 17, 2019
PubMed

Insights

Researchers developed novel nicotinamide derivatives targeting Aurora kinases (Aur A/B) to combat cancer. Compound 10l demonstrated potent inhibition of Aur A and significant antitumor activity in cell lines, outperforming reference drugs.

Area of Science:

  • Medicinal Chemistry
  • Cancer Biology
  • Molecular Pharmacology

Background:

  • Aurora kinases (Aur A/B) are frequently overexpressed in solid tumors.
  • These kinases play crucial roles in oncogenesis and tumor progression.
  • Targeting Aurora kinases is a promising strategy for cancer therapy.

Purpose of the Study:

  • To synthesize and evaluate novel nicotinamide derivatives as Aurora kinase inhibitors.
  • To assess the in vitro antitumor activity of these compounds against various cancer cell lines.
  • To investigate the antiproliferative, cytotoxic, and apoptotic effects of lead compounds.

Main Methods:

  • Synthesis of a series of nicotinamide derivatives.
  • Evaluation of kinase inhibitory activity against Aurora A (Aur A) and Aurora B (Aur B).
  • In vitro assessment of antitumor activity, antiproliferation, cytotoxicity, and apoptosis in SW620, HT-29, NCI-H1975, and Hela cancer cell lines.
  • Binding mode analysis of the most potent inhibitor.

Main Results:

  • Compound 10l, a potent Aur A inhibitor, exhibited significant antitumor activity against SW620 and NCI-H1975 cell lines (IC50 values of 0.61 and 1.06 μM).
  • Compound 10l demonstrated superior efficacy compared to the reference compound (IC50 values of 3.37 and 6.67 μM).
  • Binding mode studies revealed favorable interactions between compound 10l and Aur A.

Conclusions:

  • Nicotinamide derivative 10l is a highly effective inhibitor of Aur A with potent anticancer properties.
  • Compound 10l shows promise as a therapeutic agent for solid tumors overexpressing Aurora kinases.
  • Further investigation into compound 10l is warranted for cancer treatment development.
Keywords:
AntitumorAurora kinasesKinase inhibitorsNicotinamideSAR

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