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

Pelin Kaya, Elisabeth Schaffner-Reckinger, Ganesh babu Manoharan, Vladimir Vukic, Alexandros Kiriazis, Mirko Ledda, Maria Burgos Renedo, Karolina Pavic, Anthoula Gaigneaux, Enrico Glaab, Daniel Kwaku Abankwa*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)8569-8584
Number of pages16
JournalJournal of Medicinal Chemistry
Volume67
Issue number11
DOIs
Publication statusPublished - 13 Jun 2024
Externally publishedYes

Keywords

  • Antineoplastic Agents/pharmacology
  • Animals
  • Humans
  • Proto-Oncogene Proteins p21(ras)/genetics
  • Cyclic Nucleotide Phosphodiesterases, Type 6/antagonists & inhibitors
  • Sildenafil Citrate/pharmacology
  • Cell Line, Tumor
  • Structure-Activity Relationship
  • Cell Proliferation/drug effects
  • Mutation
  • Phosphodiesterase Inhibitors/pharmacology

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