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
  • 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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