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PROTAC-Mediated Selective Degradation of Cytosolic Soluble Epoxide Hydrolase Enhances ER Stress Reduction. 2023

Yuxin Wang, and Christophe Morisseau, and Akihiro Takamura, and Debin Wan, and Dongyang Li, and Simone Sidoli, and Jun Yang, and Dennis W Wolan, and Bruce D Hammock, and Seiya Kitamura
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, One Shields Avenue, Davis, California 95616, United States.

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme responsible for lipid metabolism and is a promising drug target. Here, we report the first-in-class PROTAC small-molecule degraders of sEH. Our optimized PROTAC selectively targets the degradation of cytosolic but not peroxisomal sEH, resulting in exquisite spatiotemporal control. Remarkably, our sEH PROTAC molecule has higher potency in cellular assays compared to the parent sEH inhibitor as measured by the significantly reduced ER stress. Interestingly, our mechanistic data indicate that our PROTAC directs the degradation of cytosolic sEH via the lysosome, not through the proteasome. The molecules presented here are useful chemical probes to study the biology of sEH with the potential for therapeutic development. Broadly, our results represent a proof of concept for the superior cellular potency of sEH degradation over sEH enzymatic inhibition, as well as subcellular compartment-selective modulation of a protein by PROTACs.

UI MeSH Term Description Entries
D003600 Cytosol Intracellular fluid from the cytoplasm after removal of ORGANELLES and other insoluble cytoplasmic components. Cytosols
D004851 Epoxide Hydrolases Enzymes that catalyze reversibly the formation of an epoxide or arene oxide from a glycol or aromatic diol, respectively. Epoxide Hydrase,Epoxide Hydrases,Epoxide Hydratase,Epoxide Hydratases,Epoxide Hydrolase,9,10-Epoxypalmitic Acid Hydrase,Microsomal Epoxide Hydrolase,Styrene Epoxide Hydrolase,9,10 Epoxypalmitic Acid Hydrase,Acid Hydrase, 9,10-Epoxypalmitic,Epoxide Hydrolase, Microsomal,Epoxide Hydrolase, Styrene,Hydrase, 9,10-Epoxypalmitic Acid,Hydrase, Epoxide,Hydrases, Epoxide,Hydratase, Epoxide,Hydratases, Epoxide,Hydrolase, Epoxide,Hydrolase, Microsomal Epoxide,Hydrolase, Styrene Epoxide,Hydrolases, Epoxide
D000094243 Proteolysis Targeting Chimera Bifunctional molecules that are designed to recruit E3 UBIQUITIN LIGASE to a specific target protein. Proteolysis targeting chimera consist of a target protein ligand connected via a linker to an E3 ligand. They promote association of E3 with specific target proteins tagged for degradation via the PROTEASOME. Cereblon-Based Small-Molecule Compounds,IAP-Based PROTACs,MDM2 Protein-Based PROTACs,PROTAC Proteolysis Targeting Chimera,PROTACs,Phospho-Dependent PROTACs,PhosphoPROTACs,Proteolysis Targeting Chimeras,VHL-Based PROTACs,Cereblon Based Small Molecule Compounds,Chimeras, Proteolysis Targeting,IAP Based PROTACs,MDM2 Protein Based PROTACs,Phospho Dependent PROTACs,Targeting Chimeras, Proteolysis,VHL Based PROTACs
D059865 Endoplasmic Reticulum Stress Various physiological or molecular disturbances that impair ENDOPLASMIC RETICULUM function. It triggers many responses, including UNFOLDED PROTEIN RESPONSE, which may lead to APOPTOSIS; and AUTOPHAGY. Stress, Endoplasmic Reticulum,Endoplasmic Reticulum Stresses,Reticulum Stress, Endoplasmic,Reticulum Stresses, Endoplasmic,Stresses, Endoplasmic Reticulum

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