Design, Synthesis, and Activity Evaluation of BRD4 PROTAC Based on Alkenyl Oxindole-DCAF11 Pair

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 (<b>8a</b>-<b>8o</b>, <b>14a-14f</b>, <b>22a-22m</b>) with modified alkenyl oxindole warheads and developed a high-throughput screening system based on high-content imaging. We identified <b>L134</b> (<b>22a</b>) as a potent BRD4 degrader, achieving BRD4 degradation (<i>D</i>_max > 98%, DC₅₀ = 7.36 nM) and demonstrating antitumor activity. Mechanically, BRD4 degradation by <b>L134</b> 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 <b>L134</b> based on alkenyl oxindole-DCAF11 pair as a promising candidate for treating BRD4-driven cancers.