Development of a genetically encoded and potent PDE6D inhibitor

Gomez-Mulas, A.; Schaffner-Reckinger, E.; Peeters, H.; Chippalkatti, R.; Dautbasic, A.; Smith, M. J.; Ismail, S.; Abankwa, D. K.

doi:10.1101/2025.09.29.679187

bioRxiv · 10.1101/2025.09.29.679187

Development of a genetically encoded and potent PDE6D inhibitor

Gomez-Mulas, A.·Schaffner-Reckinger, E.·Peeters, H.·Chippalkatti, R.·Dautbasic, A.·Smith, M. J.·Ismail, S.·Abankwa, D. K.

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Abstract

PDE6D is a trafficking chaperone of prenylated proteins, such as small GTPases. Several small molecule inhibitors have been developed against it, given that the oncogene K-Ras is one of the cargo proteins. Inhibitor development suffered from the fact that inhibitors against the hydrophobic pocket of PDE6D were typically poorly water-soluble. Here we describe the development of genetically encoded inhibitors that are inspired by high-affinity natural cargo of PDE6D. Our most potent inhibitor, SNAP-STI, encodes merely a farnesylated tetra-peptide, which efficiently blocks PDE6D binding of farnesylated cargo. Direct comparison with small molecule PDE6D inhibitors suggests its higher potency. We show that inhibition of K-Ras membrane anchorage and K-RasG12C-dependent MAPK-signaling by SNAP-STI is weak, consistent with what is observed after PDE6D knockdown. Our data therefore further support that PDE6D is not a suitable surrogate target for efficient inhibition of K-Ras membrane anchorage and MAPK-activity. Nonetheless, by exploiting contacts at the pocket entry, we established a generalizable strategy to design high-affinity PDE6D inhibitors, providing powerful tools for PDE6D biology and target validation.

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Gomez-Mulas, A., Schaffner-Reckinger, E., Peeters, H., Chippalkatti, R., Dautbasic, A., Smith, M. J., Ismail, S., Abankwa, D. K.. 2025-09-30. Development of a genetically encoded and potent PDE6D inhibitor. https://doi.org/10.1101/2025.09.29.679187

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