Nakane Keita, Morisseau Christophe, Dowker-Key Presley D, Benitez Gabrielle, Aguilan Jennifer T, Nagai Emiko, Sidoli Simone, Hammock Bruce D, Bettaieb Ahmed, Shinoda Kosaku, Kitamura Seiya
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, United States.
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, One Shields Avenue, Davis, California 95616, United States.
ACS Med Chem Lett. 2024 Oct 3;15(11):1891-1898. doi: 10.1021/acsmedchemlett.4c00357. eCollection 2024 Nov 14.
Soluble epoxide hydrolase (sEH) is a bifunctional enzyme involved in fatty acid metabolism and a promising drug target. We previously reported first-generation sEH proteolysis-targeting chimeras (PROTACs) with limited degradation potency and low aqueous and metabolic stability. Herein, we report the development of next-generation sEH PROTAC molecules with improved stability and degradation potency. One of the most potent molecules (compound ) exhibits a half-maximal degradation concentration in the sub-nM range, is stable , and effectively degrades sEH in mouse livers and brown adipose tissues. Given the role played by sEH in many metabolic and nonmetabolic diseases, the presented molecules provide useful chemical probes for the study of sEH biology. They also hold potential for therapeutic development against a range of disease conditions, including diabetes, inflammation, and metabolic disorders.
可溶性环氧化物水解酶（sEH）是一种参与脂肪酸代谢的双功能酶，也是一个很有前景的药物靶点。我们之前报道过第一代sEH蛋白水解靶向嵌合体（PROTACs），其降解效力有限，且在水性和代谢方面稳定性较低。在此，我们报道了具有更高稳定性和降解效力的下一代sEH PROTAC分子的研发情况。其中最有效的一种分子（化合物 ）在亚纳摩尔范围内表现出半数最大降解浓度，稳定性良好，并且能在小鼠肝脏和棕色脂肪组织中有效降解sEH。鉴于sEH在许多代谢性和非代谢性疾病中所起的作用，所展示的这些分子为研究sEH生物学提供了有用的化学探针。它们在针对一系列疾病状况（包括糖尿病、炎症和代谢紊乱）的治疗开发方面也具有潜力。
