ArticleNature communications2022
A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 102 papers.
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Who cites it
102 citing papers in PubMed, 197 citations in OpenAlex.
- Evolving CRBN ligands enhance the drug-like properties of protein degraders.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- A DoE-Dual centrifugation-driven screening platform for liposomal incorporation of poorly soluble APIs: Application to the PROTAC ACBI2.International journal of pharmaceutics: X · 2026Article
- Unique fluoroalkyl substituents: is there life after CFChemical science · 2026Review
- A bivalent molecular glue linking lysine acetyltransferases to oncogene-induced cell death.Cell · 2026Article
- COMPASS: A Computational Pipeline to Identify Linkers Predicting Ubiquitinable PROTAC-Induced Ternary Complexes.ChemMedChem · 2026Article
- Computational mapping of productive POI-E3 ligase conformations to guide de novo degrader design: application to WEE1 and PKMYT1 PROTACs.Journal of cheminformatics · 2026Article
- Discovery of SMD-6346: A Potent, Selective, and Orally Active SMARCA2 Degrader for Targeting SMARCA4-Deficient Human Cancers.Journal of medicinal chemistry · 2026Article
- Assays for Measuring the Cell Permeability of Proteolysis-Targeting Chimeras (PROTACs): Performance, Correlations, Applicability and Recommendations.Molecular pharmaceutics · 2026Article
- Context-dependent synthetic lethality - an emerging precision therapeutic approach.Nature reviews. Cancer · 2026Review
- Research Trends and Emerging Frontiers in Proteolysis Targeting Chimeras (PROTACs): A Bibliometric Analysis of 2630 Publications (2001-2025).Pharmaceuticals (Basel, Switzerland) · 2026Article
- Structural basis for selective and potent degradation of IRAK4 by KT-474.Nature communications · 2026Article
- Methods to Study the Molecular Mechanism and Drive the Design of Protein Degraders.Chemical reviews · 2026Review
- Ratiometric transcriptional activation by protein degradation.bioRxiv : the preprint server for biology · 2026Article
- Article
- Targeted regeneration of post-radiation epithelium without promoting cancer recurrence.Research square · 2026Article
- Lessons learned in linking PROTACs from discovery to the clinic.Nature reviews. Chemistry · 2026Review
- Allosteric PROTACs: Expanding the Horizon of Targeted Protein Degradation.Journal of the American Chemical Society · 2026Review
- A Gold-PROTAC Degrades the Oncogenic Tyrosine Kinase MERTK: Insights into the Degradome from a Steady-State System.ACS chemical biology · 2026Article
- Synthetic lethality in cancer drug discovery: challenges and opportunities.Nature reviews. Drug discovery · 2026Review
- Synthetic lethality in cancer therapy: Mechanisms, models and clinical translation for overcoming therapeutic resistance.Clinical and translational medicine · 2026Review
42 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
30 authors at 3 institutions in 4 countries.
Funding
Abstract
Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target protein and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. In the clinic, the oral route of administration is the option of choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4-deficient cancers. Here we outline structure- and property-guided approaches that led to orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.