| Autor: |
Zhao, Man, Ma, Wenjing, Liang, Jinyi, Xie, Yubao, Wei, Tianzi, Zhang, Ming, Qin, Jiajie, Lao, Lingyin, Tian, Ruilin, Wu, Haiqiang, Cheng, Jin, Li, Min, Liu, Yuyang, Hong, Liang, Li, Guofeng |
| Zdroj: |
Journal of Medicinal Chemistry; November 2024, Vol. 67 Issue: 21 p19428-19447, 20p |
| Abstrakt: |
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 (8a–8o, 14a–14f, 22a–22m) with modified alkenyl oxindole warheads and developed a high-throughput screening system based on high-content imaging. We identified L134(22a) as a potent BRD4 degrader, achieving BRD4 degradation (Dmax> 98%, DC50= 7.36 nM) and demonstrating antitumor activity. Mechanically, BRD4 degradation by L134was 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 L134based on alkenyl oxindole-DCAF11 pair as a promising candidate for treating BRD4-driven cancers. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
