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

Wang，Ying1; Wei，Tianzi2; Zhao，Man1; Huang，Aima3; Sun，Fan3; Chen，Lu1; Lin，Risheng2; Xie，Yubao1; Zhang，Ming1; Xu，Shiyu3; Sun，Zhihui3; Hong，Liang3; Wang，Rui1,4; Tian，Ruilin2; Li，Guofeng1

2024-05-01

10.1371/journal.pbio.3002550

PLoS Biology   影响因子和分区

1544-9173

1545-7885

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.

SCI

英语

其他

BIOLOGY & BIOCHEMISTRY

2-s2.0-85193579120

Scopus

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,Research Unit of Peptide Science,Chinese Academy of Medical Sciences,Peking Union Medical College,Beijing,China

Wang，Ying,Wei，Tianzi,Zhao，Man,et al. Alkenyl oxindole is a novel PROTAC moiety that recruits the CRL4DCAF11 E3 ubiquitin ligase complex for targeted protein degradation[J]. PLoS Biology,2024,22(5 May).

Wang，Ying.,Wei，Tianzi.,Zhao，Man.,Huang，Aima.,Sun，Fan.,...&Li，Guofeng.(2024).Alkenyl oxindole is a novel PROTAC moiety that recruits the CRL4DCAF11 E3 ubiquitin ligase complex for targeted protein degradation.PLoS Biology,22(5 May).

Wang，Ying,et al."Alkenyl oxindole is a novel PROTAC moiety that recruits the CRL4DCAF11 E3 ubiquitin ligase complex for targeted protein degradation".PLoS Biology 22.5 May(2024).