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Design, Optimization and Mechanistic Insights Into Terpenoid-Derived Inhibitors of Protein Kinase C Iota

Rachid Chahboun1, Fernando Rodríguez-Serrano2,3, Ángel Bueno1

  • 1Department of Organic Chemistry, Faculty of Sciences, Institute of Biotechnology, University of Granada, Granada, Spain.

Chemical Biology & Drug Design
|June 26, 2026
PubMed

Insights

Meroxest inhibits Protein Kinase C iota (PKCι), a cancer-associated kinase. Further optimization of meroxest analogues, like compound 19, may yield improved PKCι inhibitors for cancer therapy.

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Cancer Biology

Background:

  • Protein kinase C iota (PKCι) is an atypical isoform implicated in cancer development and therapy resistance.
  • Meroxest, a synthetic naphthoquinone, exhibits antitumor effects but its precise mechanism remains unclear.

Purpose of the Study:

  • To identify the kinase targets of meroxest and explore its structure-activity relationship (SAR) for Protein Kinase C iota (PKCι).
  • To guide the development of novel PKCι inhibitors for cancer treatment.

Main Methods:

  • Kinase profiling of meroxest against a 410-kinase panel.
  • Synthesis of meroxest analogues for SAR studies.
  • Molecular docking to predict binding mode within the PKCι catalytic site.
  • Biochemical assays to evaluate inhibitory activity.

Main Results:

  • Meroxest significantly inhibited PKCι (52% residual activity) and Cdc7/cyclin B1 (63% residual activity) at 10 μM, with PKCι being the most affected kinase.
  • Docking studies suggested an ATP-competitive binding mode for meroxest in the PKCι active site.
  • Compound 19, a meroxest analogue lacking a methyl group, showed a modest improvement in PKCι inhibition.

Conclusions:

  • PKCι is a primary target identified from meroxest's kinase profile.
  • Compound 19 represents a promising scaffold for developing more potent PKCι inhibitors.
  • Further optimization and cell-based validation are necessary to develop effective cancer therapeutics.
Keywords:
cancer drug discoverykinase inhibitionmolecular dockingprotein kinase C iota (PKCι)structure–activity relationship (SAR)

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