ArticleNature communications2025
Mode of action of a DCAF16-recruiting targeted glue that can selectively degrade BRD9.
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
- BRD9 Degraders Unleash GBAF Chromatin Remodeling Activity in Synovial Sarcoma.Cancer research · 2026Article
- Targeted Lysosomal Degradation of Extracellular and Membrane Proteins: From Receptor Hijacking to Programmable Endolysosomal Routing.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Ubiquitin family as novel protein partners for molecular glues.npj drug discovery · 2026Review
- Induced ubiquitination of the partially disordered estrogen receptor alpha via a 14-3-3 directed molecular glue-PROTAC.Nature communications · 2026Article
- Eyes Toward the Clinic: Selective Inhibition and Degradation Approaches to Bromodomain-Containing Proteins.Chembiochem : a European journal of chemical biology · 2026Review
- Covalent Reprogramming of Kinase Binders to Modulate Protein Abundance.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Methods to Study the Molecular Mechanism and Drive the Design of Protein Degraders.Chemical reviews · 2026Review
- Discovery and Structural Optimization of BRD4-Selective Monovalent Direct Degraders.ACS medicinal chemistry letters · 2026Article
- Targeting "undruggable" cancer proteins: pharmacological challenges and emerging strategies.Translational cancer research · 2026Review
- Review
- From Serendipity to Strategy: Rationalizing Molecular Glue Discovery and Proximity-Induced Pharmacology through Chemical Biology.Journal of the American Chemical Society · 2026Review
- Covalent Reprogramming of Kinase Binders to Modulate Protein Homeostasis.bioRxiv : the preprint server for biology · 2025Article
Corrections and comments
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Authors and funding
23 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Molecular glue degraders for therapeutic target proteins are emerging as a strategy in drug discovery. Here, we modify a BRD9 ligand with specific chemical fragments to create degrader compounds that we call Targeted Glues. When bound to the target protein, these create an altered protein-ligand interface that is recognised by a ligase. This interaction between the target and the E3 ligase leads to protein degradation and is stabilised by a reversible covalent interaction between our molecule and a specific cysteine in the ligase. By screening a library of BRD9 targeted compounds we discover AMPTX1, a potent selective and reversibly covalent BRD9 degrader. In cells, AMPTX-1 selectively recruits the E3 ligase, DCAF16, to BRD9 and drives BRD9 degradation, as demonstrated by co-immunoprecipitation-mass spectrometry. BRD9 degradation is primarily dependent on the engagement of the surface Cys58 of DCAF16; the formation of a covalent adduct to DCAF16 is facilitated by ternary complex formation with BRD9. BRD9 degradation is also achieved in vivo with AMPTX-1 in a mouse xenograft model after oral dosing due to the drug-like, orally bioavailable properties of the compound. This supports the concept that covalent recruitment of DCAF16 is a viable approach in the development of therapeutic degraders.
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