Development of a PDEδ‐Targeting PROTACs that Impair Lipid Metabolism

The prenyl-protein chaperone PDEdelta modulates the localization of lipidated proteins in the cell, but current knowledge about its biological function is limited. Small-molecule inhibitors that target the PDEdelta prenyl-binding site have proven invaluable in the analysis of biological processes mediated by PDEdelta, like KRas cellular trafficking. However, allosteric inhibitor release from PDEdelta by the Arl2/3 GTPases limits their application. We describe the development of new proteolysis-targeting chimeras (PROTACs) that efficiently and selectively reduce PDEdelta levels in cells through induced proteasomal degradation. Application of the PDEdelta 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 PDEdelta function plays a role in the regulation of enzymes of the mevalonate pathway.