Design, Synthesis, and Activity Evaluation of BRD4 PROTAC Based on Alkenyl Oxindole-DCAF11 Pair
Man Zhao, Wenjing Ma, Jinyi Liang, Yubao Xie, Tianzi Wei, Ming Zhang, Jiajie Qin, Lingyin Lao, Ruilin Tian, Haiqiang Wu, Jin Cheng, Min Li, Yuyang Liu, Liang Hong, Guofeng Li
Abstract
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 ( D max > 98%, DC 50 = 7.36 nM) and demonstrating antitumor activity. Mechanically, BRD4 degradation by L134 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 L134 based on alkenyl oxindole-DCAF11 pair as a promising candidate for treating BRD4-driven cancers.