Sun Tao, Zhai Shiyang, König Beate, Honin Irina, Kponomaizoun Cindy-Esther, Hansen Finn K
Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, 53121 Bonn, Germany.
ACS Med Chem Lett. 2025 May 20;16(6):1155-1162. doi: 10.1021/acsmedchemlett.5c00193. eCollection 2025 Jun 12.
Targeted protein degradation (TPD) through heterobifunctional molecules to initiate ubiquitination and facilitate subsequent degradation has emerged as a powerful therapeutic strategy. Most heterobifunctional molecules designed for TPD function primarily through a limited set of E3 ligases, which restricts this therapeutic approach to specific tissues that express the necessary ligases. Herein, we have developed a novel series of heterobifunctional bypassing E3 targeting chimeras (BYETACs) for the targeted degradation of histone deacetylases (HDACs). To this end, a ubiquitin-specific protease 14 (USP14) inhibitor is utilized for the first time as a novel ligand that can directly bind to the 26S proteasome subunit RPN1. Subsequent conjugation of the USP14 ligand with the HDAC inhibitor vorinostat yielded HDAC BYETACs that effectively and preferentially reduced HDAC1 protein levels in multiple myeloma MM.1S cells.
通过异双功能分子启动泛素化并促进后续降解的靶向蛋白质降解（TPD）已成为一种强大的治疗策略。大多数为TPD设计的异双功能分子主要通过有限的一组E3连接酶发挥作用，这将这种治疗方法限制在表达必要连接酶的特定组织中。在此，我们开发了一系列新型的异双功能绕过E3靶向嵌合体（BYETACs），用于靶向降解组蛋白脱乙酰酶（HDACs）。为此，首次将泛素特异性蛋白酶14（USP14）抑制剂用作一种新型配体，它可以直接与26S蛋白酶体亚基RPN1结合。随后将USP14配体与HDAC抑制剂伏立诺他偶联，得到了HDAC BYETACs，其可有效且优先降低多发性骨髓瘤MM.1S细胞中HDAC1蛋白水平。
