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Discovery of new pyrazole-4-carboxamide analogues as potential anticancer agents targeting dual aurora kinase A and B

Digambar Yevale1, Nishith Teraiya2, Twinkle Lalwani3

  • 1Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China; Department of Chemistry, Shri M.M Patel Institute of Sciences and Research, Kadi Sarva Vishwavidyalaya, Gandhinagar, Gujarat, 382016, India.

European Journal of Medicinal Chemistry
|October 10, 2024
PubMed

Insights

New pyrazole-4-carboxamide analogues were developed as anticancer agents. Compound 6k effectively inhibited Aurora kinases A and B, leading to cell cycle arrest, apoptosis, and promising anticancer effects in vitro.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Aurora kinases A and B are crucial for cell division and are implicated in cancer development.
  • Inhibiting Aurora kinases is a promising anticancer strategy.
  • Novel kinase inhibitors are needed to target these pathways.

Purpose of the Study:

  • To discover and evaluate new pyrazole-4-carboxamide analogues as Aurora kinase inhibitors.
  • To assess the anticancer activity and mechanism of action of these compounds.
  • To investigate the druggability and in vitro stability of lead compounds.

Main Methods:

  • Synthesis and chemical characterization of pyrazole-4-carboxamide analogues.
  • In vitro kinase inhibition assays for Aurora kinases A and B.
  • Cytotoxicity assays against HeLa and HepG2 cancer cell lines.
  • Cell cycle analysis, apoptosis assays, and Western blotting.
  • Molecular docking and molecular dynamics simulations.
  • In vitro metabolic stability assays.

Main Results:

  • Compound 6k exhibited potent and selective inhibition of Aurora kinases A and B (IC50 values in nM range).
  • 6k demonstrated significant cytotoxicity against HeLa and HepG2 cells (IC50 values in μM range).
  • Mechanism of action involves cell cycle arrest at G2/M phase, induction of polyploidization, abnormal mitosis, and apoptosis via the intrinsic pathway.
  • Molecular simulations supported the kinase inhibition mechanism.
  • 6k showed favorable drug-likeness and in vitro metabolic stability.

Conclusions:

  • Compound 6k is a potent inhibitor of Aurora kinases A and B with significant in vitro anticancer activity.
  • 6k's mechanism involves cell cycle disruption and apoptosis induction.
  • The favorable drug-likeness and stability of 6k suggest its potential for further preclinical development.
Keywords:
ApoptosisAurora kinase A/B inhibitorsDockingMetabolic stability

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