Structure-Based Design of PROTACS for the Degradation of Soluble Epoxide Hydrolase

The bifunctional soluble epoxide hydrolase (sEH) represents
a promising
target for inflammation-related diseases. Although potent inhibitors
targeting each domain are available, sEH-PROTACs offer the unique
ability to simultaneously block both enzymatic functions, mimicking
the sEH knockout phenotype, which has been associated with reducing
inflammation, including neuroinflammation, and delaying the progression
of Alzheimer’s disease. Herein, we report the structure-based
development of a potent sEH-PROTAC as a useful pharmacological tool.
In order to facilitate a rapid testing of the PROTACs, a cell-based
sEH degradation assay was developed utilizing HiBiT technology. We
designed and synthesized 24 PROTACs. Furthermore, cocrystallization
of sEH with two selected PROTACs allowed us to explore the binding
mode and rationalize the most optimal linker length. After comprehensive
biological and physicochemical characterization of this series, the
most optimal PROTAC 23 was identified in primary human
and murine cells, highlighting the potential of using 23 in disease-relevant cell and tissue models.