Chen Li, Deng Zhijie, Xiong Yan, Liu Jing, Huang Daoyuan, Wang Jingchao, Chen Yong, Inuzuka Hiroyuki, Xie Ling, Chen Xian, Jin Jian, Wei Wenyi
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, United States.
Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
J Am Chem Soc. 2025 Aug 20;147(33):29875-29883. doi: 10.1021/jacs.5c06306. Epub 2025 Aug 6.
Targeted protein stabilization has emerged as a promising therapeutic strategy to combat various human diseases linked to aberrant protein degradation. However, the deubiquitinase-targeting chimera (DUBTAC) technology is still in its infancy, with only a few proteins being successfully stabilized. To this end, the stabilization of tumor suppressor proteins represents a critical therapeutic strategy to combat cancer, as their loss-of-function mutations and reduced expression are frequently implicated in the pathogenesis of diverse types of human cancer. In this study, we present an innovative PRO-DUBTAC platform that, for the first time, stabilizes tumor-suppressive E3 ubiquitin ligases as a novel anticancer therapeutic approach. Through the conjugation of E3 ligase ligands with a small-molecule ligand of the deubiquitinase OTUB1 a linker, we developed two series of PRO-DUBTACs─VHL-DUBTAC and KEAP1-DUBTAC─that effectively stabilize the tumor-suppressive E3 ligases VHL and KEAP1 in cells, respectively, in an OTUB1-dependent manner to retard tumor cell growth. PRO-DUBTAC could be a versatile and generalizable platform for the selective stabilization of tumor-suppressor E3 ligases, thereby opening new therapeutic avenues for targeted cancer therapies by harnessing the tumor-suppressive potential of E3 ligases.
靶向蛋白稳定化已成为一种有前景的治疗策略，用于对抗与异常蛋白降解相关的各种人类疾病。然而，去泛素酶靶向嵌合体（DUBTAC）技术仍处于起步阶段，仅有少数蛋白质被成功稳定化。为此，稳定肿瘤抑制蛋白是对抗癌症的关键治疗策略，因为它们的功能丧失突变和表达降低常常与多种人类癌症的发病机制有关。在本研究中，我们提出了一种创新的PRO-DUBTAC平台，该平台首次将肿瘤抑制性E3泛素连接酶稳定化，作为一种新型抗癌治疗方法。通过将E3连接酶配体与去泛素酶OTUB1的小分子配体通过一个连接子进行偶联，我们开发了两个系列的PRO-DUBTAC——VHL-DUBTAC和KEAP1-DUBTAC——它们分别以OTUB1依赖的方式在细胞中有效稳定肿瘤抑制性E3连接酶VHL和KEAP1，从而抑制肿瘤细胞生长。PRO-DUBTAC可能是一个通用且可推广的平台，用于选择性稳定肿瘤抑制性E3连接酶，从而通过利用E3连接酶的肿瘤抑制潜力为靶向癌症治疗开辟新的治疗途径。
