PDF(Pubmed)
Abstract：
Alkenyl oxindoles have been characterized as autophagosome-tethering compounds (ATTECs), which can target mutant huntingtin protein (mHTT) for lysosomal degradation. In order to expand the application of alkenyl oxindoles for targeted protein degradation, we designed and synthesized a series of heterobifunctional compounds by conjugating different alkenyl oxindoles with bromodomain-containing protein 4 (BRD4) inhibitor JQ1. Through structure-activity relationship study, we successfully developed JQ1-alkenyl oxindole conjugates that potently degrade BRD4. Unexpectedly, we found that these molecules degrade BRD4 through the ubiquitin-proteasome system, rather than the autophagy-lysosomal pathway. Using pooled CRISPR interference (CRISPRi) screening, we revealed that JQ1-alkenyl oxindole conjugates recruit the E3 ubiquitin ligase complex CRL4DCAF11 for substrate degradation. Furthermore, we validated the most potent heterobifunctional molecule HL435 as a promising drug-like lead compound to exert antitumor activity both in vitro and in a mouse xenograft tumor model. Our research provides new employable proteolysis targeting chimera (PROTAC) moieties for targeted protein degradation, providing new possibilities for drug discovery.
摘要：
链烯基氧吲哚被表征为自噬体系链化合物（ATTECs），它可以靶向突变型亨廷顿蛋白（mHTT）进行溶酶体降解。为了扩大链烯基羟吲哚在蛋白质靶向降解中的应用,我们通过将不同的烯基羟吲哚与含溴结构域的蛋白4（BRD4）抑制剂JQ1缀合，设计并合成了一系列异双功能化合物。通过构效关系研究,我们成功开发了能有效降解BRD4的JQ1-链烯基羟吲哚偶联物。出乎意料的是,我们发现这些分子通过泛素-蛋白酶体系统降解BRD4，而不是自噬-溶酶体途径。使用汇集的CRISPR干扰（CRISPRi）筛选，我们揭示了JQ1-链烯基羟吲哚缀合物募集E3泛素连接酶复合物CRL4DCAF11用于底物降解。此外，我们验证了最有效的异双功能分子HL435是一种有前景的药物样先导化合物,可在体外和小鼠异种移植肿瘤模型中发挥抗肿瘤活性.我们的研究提供了新的可用蛋白水解靶向嵌合体（PROTAC）部分用于靶向蛋白质降解，为药物发现提供了新的可能性。
