2. Academic Validation
  3. An Improved PDE6D Inhibitor Combines with Sildenafil To Inhibit KRAS Mutant Cancer Cell Growth

An Improved PDE6D Inhibitor Combines with Sildenafil To Inhibit KRAS Mutant Cancer Cell Growth

  • J Med Chem. 2024 Jun 13;67(11):8569-8584. doi: 10.1021/acs.jmedchem.3c02129.
Pelin Kaya 1,  Elisabeth Schaffner-Reckinger 1,  Ganesh Babu Manoharan 1,  Vladimir Vukic 2,  Alexandros Kiriazis 3,  Mirko Ledda 4,  Maria Burgos Renedo 1,  Karolina Pavic 1,  Anthoula Gaigneaux 5,  Enrico Glaab 4,  Daniel Kwaku Abankwa 1 3
Affiliations

Affiliations

  • 1 Cancer Cell Biology and Drug Discovery Group, Department of Life Sciences and Medicine, University of Luxembourg, 4365 Esch-sur-Alzette, Luxembourg.
  • 2 Faculty of Technology, University of Novi Sad, 21000 Novi Sad, Serbia.
  • 3 Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
  • 4 Luxembourg Center for Systems Biomedicine, University of Luxembourg, 4365 Esch-sur-Alzette, Luxembourg.
  • 5 Bioinformatics Core, Department of Life Sciences and Medicine, University of Luxembourg, 4365 Esch-sur-Alzette, Luxembourg.
PMID: 38758695 DOI: 10.1021/acs.jmedchem.3c02129
Abstract

The trafficking chaperone PDE6D (or PDEδ) was proposed as a surrogate target for K-Ras, leading to the development of a series of inhibitors that block its prenyl binding pocket. These inhibitors suffered from low solubility and suspected off-target effects, preventing their clinical development. Here, we developed a highly soluble, low nanomolar PDE6D inhibitor (PDE6Di), Deltaflexin3, which has the lowest off-target activity as compared to three prominent reference compounds. Deltaflexin3 reduces Ras signaling and selectively decreases the growth of KRAS mutant and PDE6D-dependent Cancer cells. We further show that PKG2-mediated phosphorylation of Ser181 lowers K-Ras binding to PDE6D. Thus, Deltaflexin3 combines with the approved PKG2 activator Sildenafil to more potently inhibit PDE6D/K-Ras binding, Cancer cell proliferation, and microtumor growth. As observed previously, inhibition of Ras trafficking, signaling, and Cancer cell proliferation remained overall modest. Our results suggest reevaluating PDE6D as a K-Ras surrogate target in Cancer.

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