Department of Cell and Chemical Biology, Division of Chemical Biology and Drug Discovery, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center LUMC, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
ACS Chem Biol. 2023 Sep 15;18(9):2003-2013. doi: 10.1021/acschembio.3c00227. Epub 2023 Aug 29.
Ubiquitin thioesterase OTUB2, a cysteine protease from the ovarian tumor (OTU) deubiquitinase superfamily, is often overexpressed during tumor progression and metastasis. Development of OTUB2 inhibitors is therefore believed to be therapeutically important, yet potent and selective small-molecule inhibitors targeting OTUB2 are scarce. Here, we describe the development of an improved OTUB2 inhibitor, , comprising a chloroacethydrazide moiety that covalently reacts to the active-site cysteine residue. shows outstanding target engagement and proteome-wide selectivity in living cells. Importantly, as well as other OTUB2 inhibitors strongly induce monoubiquitination of OTUB2 on lysine 31. We present a route to future OTUB2-related therapeutics and have shown that the OTUB2 inhibitor developed in this study can help to uncover new aspects of the related biology and open new questions regarding the understanding of OTUB2 regulation at the post-translational modification level.
泛素硫酯酶 OTUB2 是卵巢肿瘤（OTU）去泛素化酶超家族中的一种半胱氨酸蛋白酶，在肿瘤进展和转移过程中常常过表达。因此，开发 OTUB2 抑制剂被认为具有重要的治疗意义，但针对 OTUB2 的有效且选择性的小分子抑制剂却很少。在这里，我们描述了一种改进的 OTUB2 抑制剂的开发，该抑制剂包含一个氯乙酰胺基部分，可与活性位点半胱氨酸残基发生共价反应。化合物 表现出出色的靶标结合和在活细胞中的全蛋白质组选择性。重要的是， 以及其他 OTUB2 抑制剂强烈诱导 OTUB2 在赖氨酸 31 上的单泛素化。我们提出了一种未来针对 OTUB2 的治疗方法，并表明本研究中开发的 OTUB2 抑制剂可以帮助揭示相关生物学的新方面，并提出关于在翻译后修饰水平上理解 OTUB2 调控的新问题。
