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

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.