An improved PDE6D inhibitor combines with Sildenafil to inhibit KRAS-mutant cancer cell growth

[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.

Research center :

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 :

Life sciences: Multidisciplinary, general & others
Human health sciences: Multidisciplinary, general & others

Author, co-author :

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.

External co-authors :

yes

Language :

English

Title :

An improved PDE6D inhibitor combines with Sildenafil to inhibit KRAS-mutant cancer cell growth

Publication date :

2024

Journal title :

Journal of Medicinal Chemistry

ISSN :

0022-2623

eISSN :

1520-4804

Volume :

in press

Issue :

in press

Pages :

in press

Peer reviewed :

Peer Reviewed verified by ORBi

Focus Area :

Systems Biomedicine

Development Goals :

3. Good health and well-being

FnR Project :

AFR 13589879
PoC20/15269106-inhibitPDE-RASv2

Funders :

FNR - Fonds National de la Recherche

Funding number :

PoC20/15269106-inhibitPDE-RASv2

Data Set :

https://doi.org/10.1021/acs.jmedchem.3c02129

Commentary :

The original publication is available at: https://doi.org/10.1021/acs.jmedchem.3c02129

Available on ORBilu :

since 21 May 2024

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Bibliography

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