Key result
PROTAC molecule 1d potently degrades soluble epoxide hydrolase to attenuate acute in vivo inflammation.
Why the study?
Soluble epoxide hydrolase is an attractive target for inflammatory disorders, and targeted protein degradation offers new opportunities to block its enzymatic function.
PROTAC molecule 1d is a highly potent soluble epoxide hydrolase degrader that effectively attenuates LPS-induced acute inflammation in vivo.
Supports sEH PROTAC development for acute inflammation; leaves open human translation and safety.
Bifunctional soluble epoxide hydrolase (sEH) represents an attractive therapeutic target for inflammation-associated disorders. Targeted protein degradation (TPD) offers new opportunities for targeting and blocking the enzymatic function of sEH, thereby ameliorating inflammation-related diseases. Herein, a diversity-oriented synthesis of 24 proteolysis-targeting chimeras (PROTACs) and 5 hydrophobic tag-targeted degraders (HyTTDs) was successfully facilitated by a Ugi-4CR reaction. Notably, the E3 ubiquitin ligase RNF126 and hydrophobic tag (HyT) ligands are delicately embedded in the degraders and exhibit moderate to good degradative activities toward sEH. After comprehensive biological screening, the PROTAC molecule 1d was found to have the highest degradation potency (DC 50 = 2.9 nM) and exhibited satisfactory degradative pharmacokinetic properties within 6 h, which further proved to significantly attenuate LPS-induced in vivo acute inflammation, highlighting its therapeutic utility.
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Yin et al. (2026) studied LPS-induced acute inflammation. PROTAC molecule 1d was evaluated on Degradation potency (DC50) (DC50 = 2.9 nM). The PROTAC molecule 1d exhibited high degradation potency against soluble epoxide hydrolase (DC50 = 2.9 nM) and significantly attenuated LPS-induced acute inflammation in vivo.
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