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.
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
J Am Chem Soc. 2021 Sep 22;143(37):15073-15083. doi: 10.1021/jacs.1c04841. Epub 2021 Sep 14.
Proteolysis targeting chimeras (PROTACs) represent a new class of promising therapeutic modalities. PROTACs hijack E3 ligases and the ubiquitin-proteasome system (UPS), leading to selective degradation of the target proteins. However, only a very limited number of E3 ligases have been leveraged to generate effective PROTACs. Herein, we report that the KEAP1 E3 ligase can be harnessed for targeted protein degradation utilizing a highly selective, noncovalent small-molecule KEAP1 binder. We generated a proof-of-concept PROTAC, MS83, by linking the KEAP1 ligand to a BRD4/3/2 binder. MS83 effectively reduces protein levels of BRD4 and BRD3, but not BRD2, in cells in a concentration-, time-, KEAP1- and UPS-dependent manner. Interestingly, MS83 degrades BRD4/3 more durably than the CRBN-recruiting PROTAC dBET1 in MDA-MB-468 cells and selectively degrades BRD4 short isoform over long isoform in MDA-MB-231 cells. It also displays improved antiproliferative activity than dBET1. Overall, our study expands the limited toolbox for targeted protein degradation.
蛋白水解靶向嵌合体（PROTACs）代表了一类很有前途的治疗模式。PROTACs 劫持 E3 连接酶和泛素-蛋白酶体系统（UPS），导致靶蛋白的选择性降解。然而，只有非常有限数量的 E3 连接酶被用于生成有效的 PROTACs。在此，我们报告 KEAP1 E3 连接酶可以被利用，通过使用高度选择性的、非共价的小分子 KEAP1 结合物来进行靶向蛋白降解。我们通过将 KEAP1 配体与 BRD4/3/2 结合物连接，生成了一个概念验证 PROTAC，MS83。MS83 能够以浓度、时间、KEAP1 和 UPS 依赖的方式有效地降低细胞中 BRD4 和 BRD3 的蛋白水平，但不降低 BRD2 的蛋白水平。有趣的是，MS83 在 MDA-MB-468 细胞中比招募 CRBN 的 PROTAC dBET1 更持久地降解 BRD4/3，并且在 MDA-MB-231 细胞中选择性地降解 BRD4 短亚型而不是长亚型。它还显示出比 dBET1 更好的抗增殖活性。总的来说，我们的研究扩展了靶向蛋白降解的有限工具包。
