ArticleNature communications2025
Rational design of potent small-molecule SMARCA2/A4 degraders acting via the recruitment of FBXO22.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Dual E3 ligase recruitment by monovalent degraders for tunable SMARCA 2/4 degradation.Nature chemical biology · 2026Article
- A tail of two ligases.Nature chemical biology · 2026Article
- Eyes Toward the Clinic: Selective Inhibition and Degradation Approaches to Bromodomain-Containing Proteins.Chembiochem : a European journal of chemical biology · 2026Review
- Aryl Aldehyde-Anchored Small Molecules Recruit FBXO22 for Targeted Degradation of NSD2.Journal of medicinal chemistry · 2026Article
- Review
- Covalent Reprogramming of Kinase Binders to Modulate Protein Abundance.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Discovery and Structural Optimization of BRD4-Selective Monovalent Direct Degraders.ACS medicinal chemistry letters · 2026Article
- Use of hydrogen deuterium exchange mass spectrometry in tandem with modern structural biology.The Biochemical journal · 2026Review
- Structural basis of NSD2 degradation via targeted recruitment of SCF-FBXO22.Nature communications · 2026Article
- Harnessing FBXO31 with Terminal Amide-Functionalized Molecules for Targeted Protein Degradation.Journal of the American Chemical Society · 2026Article
- Identification of E3 ligase substrates and PROTAC-induced ubiquitylation sites using proximity-based identification of ubiquitin sites (PrIUS).Communications biology · 2026Article
- Allosteric PROTACs: Expanding the Horizon of Targeted Protein Degradation.Journal of the American Chemical Society · 2026Review
- Covalent Reprogramming of Kinase Binders to Modulate Protein Homeostasis.bioRxiv : the preprint server for biology · 2025Article
- DCAF16-Based Covalent Degradative Handles for the Modular Design of Degraders.ACS central science · 2025Article
Corrections and comments
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Authors and funding
22 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Target-anchored monovalent degraders are more drug-like than their bivalent counterparts, Proteolysis Targeting Chimeras (PROTACs), while offering greater target specificity control than E3 ligase-anchored monovalent degraders, also known as molecular glues. However, their discovery has typically been serendipitous, and the rules governing their identification remain unclear. This study focuses on the intentional discovery of SMARCA2/A4 monovalent degraders using a library based on SMARCA2/A4 bromodomain-binding ligands. Compound G-6599 emerged as a lead candidate, showing exceptional degradation potency and specificity for SMARCA2/A4. Mechanistic studies reveal that G-6599 operates through the ubiquitin-proteasome pathway and the E3 ligase FBXO22. G-6599 promotes ternary complex formation between SMARCA2 and FBXO22 involving covalent conjugation to a cysteine residue on the latter. Unlike other recently identified FBXO22-dependent degraders, it does not require biotransformation. The selective degradation ability of G-6599, along with its unique mechanism, highlights the therapeutic potential of target-anchored monovalent degraders.
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