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 and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
J Am Chem Soc. 2022 Jul 20;144(28):12934-12941. doi: 10.1021/jacs.2c04824. Epub 2022 Jul 5.
Targeted protein degradation approaches have been widely used for degrading oncogenic proteins, providing a potentially promising therapeutic strategy for cancer treatment. However, approaches to targeting tumor suppressor proteins are very limited, and only a few agonists have been developed to date. Here, we report the development of a platform termed TF-DUBTAC, which links a DNA oligonucleotide to a covalent ligand of the deubiquitinase OTUB1 via a click reaction, to selectively stabilize tumor suppressor transcription factors. We developed three series of TF-DUBTACs, namely, FOXO-DUBTAC, p53-DUBTAC, and IRF-DUBTAC, which stabilize FOXO3A, p53, and IRF3 in cells, respectively, in an OTUB1-dependent manner. These results suggest that TF-DUBTAC is a generalizable platform to achieve selective stabilization of tumor suppressor transcription factors as a therapeutic means to suppress tumorigenesis.
靶向蛋白降解方法已被广泛用于降解致癌蛋白，为癌症治疗提供了一种有前途的潜在治疗策略。然而，靶向肿瘤抑制蛋白的方法非常有限，迄今为止仅开发了少数几种激动剂。在这里，我们报告了一种名为 TF-DUBTAC 的平台的开发，该平台通过点击反应将 DNA 寡核苷酸与去泛素化酶 OTUB1 的共价配体连接起来，以选择性地稳定肿瘤抑制转录因子。我们开发了三类 TF-DUBTAC，即 FOXO-DUBTAC、p53-DUBTAC 和 IRF-DUBTAC，它们分别以 OTUB1 依赖性方式稳定细胞中的 FOXO3A、p53 和 IRF3。这些结果表明，TF-DUBTAC 是一种可推广的平台，可实现肿瘤抑制转录因子的选择性稳定，作为抑制肿瘤发生的治疗手段。
