ArticlePLoS biology2024
Alkenyl oxindole is a novel PROTAC moiety that recruits the CRL4DCAF11 E3 ubiquitin ligase complex for targeted protein degradation.
Article in PLoS biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Delivering Degradation: Nanomedicine and Programmable Proximity Platforms for Targeted Protein Degradation.Pharmaceutics · 2026Review
- Targeted Histone Deacetylase Degradation via Chemical Induced Proximity by Direct Recruitment of the CUL4 Complex Adaptor Protein DDB1.ACS medicinal chemistry letters · 2025Article
- R406 and its structural analogs reduce SNCA/α-synuclein levels via autophagic degradation.Autophagy · 2025Article
- Targeted protein degradation for cancer therapy.Nature reviews. Cancer · 2025Review
- Replacing a Cereblon Ligand by a DDB1 and CUL4 Associated Factor 11 (DCAF11) Recruiter Converts a Selective Histone Deacetylase 6 PROTAC into a Pan-Degrader.ChemMedChem · 2025Article
- Recommended Tool Compounds: Thienotriazolodiazepines-Derivatized Chemical Probes to Target BET Bromodomains.ACS pharmacology & translational science · 2025Review
- Implications of frequent hitter E3 ligases in targeted protein degradation screens.Nature chemical biology · 2025Review
- Exploring Arylidene-Indolinone Ligands of Autophagy Proteins LC3B and GABARAP.ACS medicinal chemistry letters · 2025Article
- PROteolysis TArgeting Chimeras (PROTACs) and beyond: targeted degradation as a new path to fight microbial pathogens.FEMS microbiology reviews · 2025Review
- Covalent Proximity Inducers.Chemical reviews · 2025Review
- Exploring Arylidene-Indolinone Ligands of Autophagy Proteins LC3B and GABARAP.bioRxiv : the preprint server for biology · 2024Article
- Identification of host factors for livestock and poultry viruses: genome-wide screening technology based on the CRISPR system.Frontiers in microbiology · 2024Review
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Authors and funding
15 authors.
Funding
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.
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