Development of a PDEδ-Targeting PROTACs that Impair Lipid Metabolism

The prenyl-protein chaperone PDE delta modulates the localization of lipidated proteins in the cell, but current knowledge about its biological function is limited. Small-molecule inhibitors that target the PDE delta prenyl-binding site have proven invaluable in the analysis of biological processes mediated by PDE delta, like KRas cellular trafficking. However, allosteric inhibitor release from PDE delta by the Arl2/3 GTPases limits their application. We describe the development of new proteolysis-targeting chimeras (PROTACs) that efficiently and selectively reduce PDE delta levels in cells through induced proteasomal degradation. Application of the PDE delta PROTACs increased sterol regulatory element binding protein (SREBP)-mediated gene expression of enzymes involved in lipid metabolism, which was accompanied by elevated levels of cholesterol precursors. This finding for the first time demonstrates that PDE delta function plays a role in the regulation of enzymes of the mevalonate pathway.