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- Title
Alkenyl oxindole is a novel PROTAC moiety that recruits the CRL4<sup>DCAF11</sup> E3 ubiquitin ligase complex for targeted protein degradation.
- Authors
Wang, Ying; Wei, Tianzi; Zhao, Man; Huang, Aima; Sun, Fan; Chen, Lu; Lin, Risheng; Xie, Yubao; Zhang, Ming; Xu, Shiyu; Sun, Zhihui; Hong, Liang; Wang, Rui; Tian, Ruilin; Li, Guofeng
- 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. Targeted protein degradation strategies are promising avenues for drug development, but it is important to broaden the toolbox of E3 ligases that can be engaged. This study shows that alkenyl oxindole compounds act as novel E3 ligase ligands and recruit the CRL4-DCAF11 E3 ubiquitin ligase complex for substrate degradation.
- Subjects
PROTEOLYSIS; MOIETIES (Chemistry); BROMODOMAIN-containing proteins; HUNTINGTIN protein; MUTANT proteins; DRUG discovery; UBIQUITIN ligases; OXINDOLES
- Publication
PLoS Biology, 2024, Vol 22, Issue 5, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3002550