[en] 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.
Centre de recherche :
Faculty of Science, Technology and Medicine (FSTM) - Cancer Cell Biology and Drug Discovery (Abankwa group) Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group)
Disciplines :
Sciences du vivant: Multidisciplinaire, généralités & autres Sciences de la santé humaine: Multidisciplinaire, généralités & autres
Auteur, co-auteur :
Kaya, P.
Schaffner-Reckinger, E.
Manoharan, G.B.
Vukic, V.
Kiriazis, A.
Ledda, M.
Burgos, M.
Pavic, K.
Gaigneaux, A.
GLAAB, Enrico ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Biomedical Data Science
Abankwa, D.K.
Co-auteurs externes :
yes
Langue du document :
Anglais
Titre :
An improved PDE6D inhibitor combines with Sildenafil to inhibit KRAS-mutant cancer cell growth
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