School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China.
Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, China.
J Med Chem. 2024 Nov 14;67(21):19428-19447. doi: 10.1021/acs.jmedchem.4c01767. Epub 2024 Oct 30.
Proteolytic targeting chimera (PROTAC) represent an advanced strategy for targeting undruggable proteins, and the molecular warheads targeting E3 ligases play a crucial role. Recently, we explored an alkenyl oxindole warhead targeting the E3 ligase DCAF11 and sought to validate its potential. In this study, we synthesized a range of BRD4 PROTACs (-, , ) with modified alkenyl oxindole warheads and developed a high-throughput screening system based on high-content imaging. We identified () as a potent BRD4 degrader, achieving BRD4 degradation ( > 98%, DC = 7.36 nM) and demonstrating antitumor activity. Mechanically, BRD4 degradation by was mediated through the ubiquitin-proteasome system in a DCAF11-dependent manner. Therefore, this study provides a rapid screening method for effective PROTACs and highlights the PROTAC based on alkenyl oxindole-DCAF11 pair as a promising candidate for treating BRD4-driven cancers.
蛋白水解靶向嵌合体（PROTAC）代表了一种靶向不可成药蛋白的先进策略，而靶向 E3 连接酶的分子弹头则起着至关重要的作用。最近，我们探索了一种针对 E3 连接酶 DCAF11 的烯基吲哚酮弹头，并寻求验证其潜力。在这项研究中，我们合成了一系列带有改良烯基吲哚酮弹头的 BRD4 PROTAC（-，-，-），并开发了基于高内涵成像的高通量筛选系统。我们确定（）是一种有效的 BRD4 降解剂，可实现 BRD4 降解（>98%，DC=7.36 nM）并表现出抗肿瘤活性。在机制上，通过 DCAF11 依赖性泛素蛋白酶体系统介导了由 引起的 BRD4 降解。因此，本研究提供了一种有效的 PROTAC 快速筛选方法，并强调了基于烯基吲哚酮-DCAF11 对的 PROTAC 作为治疗 BRD4 驱动型癌症的有前途的候选物。
