TY - JOUR
T1 - PROTAC-Mediated Selective Degradation of Cytosolic Soluble Epoxide Hydrolase Enhances ER Stress Reduction
AU - Wang, Yuxin
AU - Morisseau, Christophe
AU - Takamura, Akihiro
AU - Wan, Debin
AU - Li, Dongyang
AU - Sidoli, Simone
AU - Yang, Jun
AU - Wolan, Dennis W.
AU - Hammock, Bruce D.
AU - Kitamura, Seiya
N1 - Publisher Copyright:
© 2023 American Chemical Society.
PY - 2023/4/21
Y1 - 2023/4/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85151287358&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85151287358&partnerID=8YFLogxK
U2 - 10.1021/acschembio.3c00017
DO - 10.1021/acschembio.3c00017
M3 - Article
C2 - 36947831
AN - SCOPUS:85151287358
SN - 1554-8929
VL - 18
SP - 884
EP - 896
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 4
ER -