Development of a PDEδ targeting PROTAC that impairs lipid metabolism

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