Soluble Epoxide Hydrolase PROTAC 1a

Soluble epoxide drolase (sEH) PROTAC 1a is a proteolysis-targeting chimera (PROTAC) that contains cereblon ligand 1 connected to the sEH inhibitor t-TUCB by a linker region.¹ It drives sEH degradation and selectively inhibits the drolase activity of sEH (IC₅₀ = 0.8 nM) over its phosphatase activity (IC₅₀ = >10,000 nM). sEH PROTAC 1a is also selective for the degradation of cytosolic over peroxisomal sEH and drives its degradation via the lysosome rather than the proteasome. It reduces thapsigargin-induced increases in phosphorylated inositol-requiring enzyme 1α (IRE1α) levels and X-box binding protein 1 (XBP1) splicing in HepG2 and 293T cells, indicating a reduction in ER stress.