2. Academic Validation
  3. Next generation thiazolyl ketone inhibitors of cytosolic phospholipase A2 α for targeted cancer therapy

Next generation thiazolyl ketone inhibitors of cytosolic phospholipase A2 α for targeted cancer therapy

  • Nat Commun. 2025 Jan 2;16(1):164. doi: 10.1038/s41467-024-55536-9.
Felicity J Ashcroft 1,  Asimina Bourboula 2 3,  Nur Mahammad 1,  Efrosini Barbayianni 2,  Astrid J Feuerherm 1,  Thanh Thuy Nguyen 1,  Daiki Hayashi 4,  Maroula G Kokotou 5,  Konstantinos Alevizopoulos 6,  Edward A Dennis 7 8,  George Kokotos 9 10,  Berit Johansen 11
Affiliations

Affiliations

  • 1 Department of Biology, Norwegian University of Science and Technology, Trondheim, Norway.
  • 2 Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens, Greece.
  • 3 Center of Excellence for Drug Design and Discovery, National and Kapodistrian University of Athens, Panepistimiopolis, Athens, Greece.
  • 4 Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Japan.
  • 5 Laboratory of Chemistry, Department of Food Science and Human Nutrition, Agricultural University of Athens, Athens, Greece.
  • 6 Ventac Partners, Ch. du Vallon 4, Yverdon-les-Bains, Switzerland.
  • 7 Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA, USA.
  • 8 Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, CA, USA.
  • 9 Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens, Greece. gkokotos@chem.uoa.gr.
  • 10 Center of Excellence for Drug Design and Discovery, National and Kapodistrian University of Athens, Panepistimiopolis, Athens, Greece. gkokotos@chem.uoa.gr.
  • 11 Department of Biology, Norwegian University of Science and Technology, Trondheim, Norway. berit.johansen@ntnu.no.
PMID: 39747052 DOI: 10.1038/s41467-024-55536-9
Abstract

Eicosanoids are key players in inflammatory diseases and Cancer. Targeting their production by inhibiting Group IVA cytosolic Phospholipase A2 (cPLA2α) offers a promising approach for Cancer therapy. In this study, we synthesize a second generation of thiazolyl ketone inhibitors of cPLA2α starting with compound GK470 (AVX235) and test their in vitro and cellular activities. We identify a more potent and selective lead molecule, GK420 (AVX420), which we test in parallel with AVX235 and a structurally unrelated compound, AVX002 for inhibition of cell viability across a panel of Cancer cell lines. From this, we show that activity of polycomb group repressive complex 2 is a key molecular determinant of sensitivity to cPLA2α inhibition, while resistance depends on antioxidant response pathways. Consistent with these results, we show that elevated intracellular Reactive Oxygen Species and activating transcription factor 4 target gene expression precede cell death in AVX420-sensitive T-cell acute lymphoblastic leukemia cells. Our findings imply cPLA2α may support Cancer by mitigating oxidative stress and inhibiting tumor suppressor expression and suggest that AVX420 has potential for treating acute leukemias and Other cancers that are susceptible to oxidative cell death.

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