Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, One Shields Avenue, Davis, California 95616, United States.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92037, United States.
ACS Chem Biol. 2023 Apr 21;18(4):884-896. doi: 10.1021/acschembio.3c00017. Epub 2023 Mar 22.
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.
可溶性环氧化物水解酶 (sEH) 是一种具有双重功能的酶，负责脂质代谢，是一种很有前途的药物靶点。在这里，我们报告了 sEH 的首个一类 PROTAC 小分子降解剂。我们优化的 PROTAC 选择性靶向细胞质而非过氧化物酶体 sEH 的降解，从而实现了精确的时空控制。值得注意的是，与亲本 sEH 抑制剂相比，我们的 sEH PROTAC 分子在细胞测定中具有更高的效力，这可以通过显著降低内质网应激来衡量。有趣的是，我们的机制数据表明，我们的 PROTAC 通过溶酶体而不是蛋白酶体来指导细胞质 sEH 的降解。这里呈现的分子是研究 sEH 生物学的有用化学探针，具有治疗开发的潜力。总的来说，我们的结果证明了 sEH 降解的细胞效力优于 sEH 酶抑制，以及通过 PROTAC 对蛋白质进行亚细胞区室选择性调节的概念。
