ArticleProceedings of the National Academy of Sciences of the United States of America2024
Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 20 citations in OpenAlex.
- Advancing PROTAC therapeutics through chemistry-guided design of smart delivery systems.Acta pharmacologica Sinica · 2026Review
- ATP-dependent chromatin remodelers in prostate cancer progression and therapeutic resistance.Endocrinology · 2026Review
- Cyclins and Cyclin-Dependent Kinases: Structure, Biological Functions, and Innovative Targeting Strategies in Cancer.MedComm · 2026Review
- A ligandable PNT domain establishes ERG as a directly targetable oncogenic driver in prostate cancer.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Epigenetic and chromatin remodeling mechanisms across cardiomyopathies: a comprehensive review.Epigenetics & chromatin · 2026Review
- Synthetic lethality between PBRM1 deficiency and PARP inhibitors: exploiting G2/M checkpoint arrest in colorectal cancer.Molecular medicine (Cambridge, Mass.) · 2026Article
- Methods to Study the Molecular Mechanism and Drive the Design of Protein Degraders.Chemical reviews · 2026Review
- Article
- Mitochondrial ATP production promotes T cell differentiation and function by regulating chromatin accessibility.bioRxiv : the preprint server for biology · 2026Article
- Integrated epigenetic networks in aging: from histone to RNA modifications.Journal of translational medicine · 2026Review
- Implications for clinical prognosis and target discovery of the SWI/SNF complex in genitourinary tumors.Discover oncology · 2026Review
- Construction and verification of a prognostic model for prostate cancer based on ribosome biogenesis-related genes.BMC medical genomics · 2025Article
- Targeting histone H2B acetylated enhanceosomes via p300/CBP degradation in prostate cancer.Nature genetics · 2025Article
- Characterization of PROTAC specificity and endogenous protein interactomes using ProtacID.Nature communications · 2025Article
- Targeted protein degradation for cancer therapy.Nature reviews. Cancer · 2025Review
- Discovery of Novel, Potent, and Orally Bioavailable SMARCA2 Proteolysis-Targeting Chimeras with Synergistic Antitumor Activity in Combination with Kirsten Rat Sarcoma Viral Oncogene Homologue G12C Inhibitors.Journal of medicinal chemistry · 2025Article
- Chromatin remodeling and cancer: the critical influence of the SWI/SNF complex.Epigenetics & chromatin · 2025Review
- PROteolysis TArgeting Chimeras (PROTACs) and beyond: targeted degradation as a new path to fight microbial pathogens.FEMS microbiology reviews · 2025Review
- Off-target autophagy disruption associated with a novel liver toxicity in dogs for a highly basic heterobifunctional protein degrader.Frontiers in pharmacology · 2025Article
- Epigenetics-targeted drugs: current paradigms and future challenges.Signal transduction and targeted therapy · 2024Review
Corrections and comments
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Authors and funding
29 authors at 3 institutions in 3 countries.
Funding
Abstract
Mammalian switch/sucrose nonfermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, an orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. Importantly, AU-24118 exhibited favorable pharmacokinetic profiles in preclinical analyses in mice and rats, and further toxicity testing in mice showed a favorable safety profile. As acquired resistance is common with targeted cancer therapeutics, experiments were designed to explore potential mechanisms of resistance that may arise with long-term mSWI/SNF ATPase PROTAC treatment. Prostate cancer cell lines exposed to long-term treatment with high doses of a mSWI/SNF ATPase degrader developed SMARCA4 bromodomain mutations and ABCB1 (ATP binding cassette subfamily B member 1) overexpression as acquired mechanisms of resistance. Intriguingly, while SMARCA4 mutations provided specific resistance to mSWI/SNF degraders, ABCB1 overexpression provided broader resistance to other potent PROTAC degraders targeting bromodomain-containing protein 4 and AR. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise.
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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.