Alkenyl oxindole is a novel PROTAC moiety that recruits the CRL4DCAF11 E3 ubiquitin ligase complex for targeted protein degradation

  • PLoS Biol. 2024 May 20;22(5):e3002550. doi: 10.1371/journal.pbio.3002550.
Ying Wang  1 ,  Tianzi Wei  2 ,  Man Zhao  1 ,  Aima Huang  3 ,  Fan Sun  3 ,  Lu Chen  1 ,  Risheng Lin  2 ,  Yubao Xie  1 ,  Ming Zhang  1 ,  Shiyu Xu  3 ,  Zhihui Sun  3 ,  Liang Hong  3 ,  Rui Wang  1  4 ,  Ruilin Tian  2 ,  Guofeng Li  1
Affiliations
  • 1. School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, China.
  • 2. Key University Laboratory of Metabolism and Health of Guangdong, Department of Medical Neuroscience, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
  • 3. Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
  • 4. Institute of Materia Medica and Research Unit of Peptide Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
PMID: 38768083 DOI: 10.1371/journal.pbio.3002550
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.

Products