美国西奈山伊坎医学院Jian Jin团队揭示了利用E3连接酶KEAP1进行靶向蛋白质降解。相关研究成果于2021年9月14日发表在《美国化学会杂志》。
蛋白质水解靶向嵌合体（PROTACs）是一类新的有前途的治疗方法。PROTACs操纵E3连接酶和泛素-蛋白酶体系统（UPS），导致目标蛋白的选择性降解。然而，只有数量非常有限的E3连接酶被用来产生有效的pROTAC。
该文中，研究人员发现KEAP1 E3连接酶可以利用高选择性、非共价小分子KEAP1粘合剂进行靶向蛋白质降解。通过将KEAP1配体连接到BRD4/3/2粘合剂，生成了概念验证的PROTAC，MS83。MS83以浓度、时间、KEAP1和UPS依赖的方式有效降低细胞中BRD4和BRD3的蛋白水平，但不降低BRD2的蛋白水平。有趣的是，在MDA-MB-468细胞中，MS83降解BRD4/3的持续性比CRBN补充蛋白dBET1更持久，在MDA-MB-231细胞中，MS83选择性降解BRD4短亚型而非长亚型。同时其显示出比dBET1更好的抗增殖活性。
总的来说，该研究扩展了有限的靶向蛋白质降解工具箱。
附：英文原文
Title: Harnessing the E3 Ligase KEAP1 for Targeted Protein Degradation
Author: Jieli Wei, Fanye Meng, Kwang-Su Park, Hyerin Yim, Julia Velez, Prashasti Kumar, Li Wang, Ling Xie, He Chen, Yudao Shen, Emily Teichman, Dongxu Li, Gang Greg Wang, Xian Chen, H. ümit Kaniskan, Jian Jin
Issue&Volume: September 14, 2021
Abstract: 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.
DOI: 10.1021/jacs.1c04841
Source: https://pubs.acs.org/doi/10.1021/jacs.1c04841
