TY - JOUR
T1 - An Improved PDE6D Inhibitor Combines with Sildenafil To Inhibit KRAS Mutant Cancer Cell Growth
AU - Kaya, Pelin
AU - Schaffner-Reckinger, Elisabeth
AU - Manoharan, Ganesh babu
AU - Vukic, Vladimir
AU - Kiriazis, Alexandros
AU - Ledda, Mirko
AU - Burgos Renedo, Maria
AU - Pavic, Karolina
AU - Gaigneaux, Anthoula
AU - Glaab, Enrico
AU - Abankwa, Daniel Kwaku
N1 - Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society
PY - 2024/6/13
Y1 - 2024/6/13
N2 - 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.
AB - 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.
KW - Antineoplastic Agents/pharmacology
KW - Animals
KW - Humans
KW - Proto-Oncogene Proteins p21(ras)/genetics
KW - Cyclic Nucleotide Phosphodiesterases, Type 6/antagonists & inhibitors
KW - Sildenafil Citrate/pharmacology
KW - Cell Line, Tumor
KW - Structure-Activity Relationship
KW - Cell Proliferation/drug effects
KW - Mutation
KW - Phosphodiesterase Inhibitors/pharmacology
UR - http://www.scopus.com/inward/record.url?scp=85193749420&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/38758695
U2 - 10.1021/acs.jmedchem.3c02129
DO - 10.1021/acs.jmedchem.3c02129
M3 - Article
C2 - 38758695
AN - SCOPUS:85193749420
SN - 0022-2623
VL - 67
SP - 8569
EP - 8584
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 11
ER -