ArticleCell chemical biology2024
Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer.
Article in Cell chemical biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- SMARCA4-Directed Treatment in Oncology Clinical Trials: A Review.Journal of immunotherapy and precision oncology · 2026Review
- AI-Driven Combination Therapy for Counteracting Dysregulated Genes in Lung Adenocarcinoma: Contribution-Aware Metaheuristic for Drug Repurposing.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Rewiring Adipocyte Plasticity: The Redox-Mitochondrial Axis as a Driver of Beige Fat Immunometabolism and Adipose Inflammation.Biomolecules · 2026Review
- Article
- Induction of complete pathological response by immunochemotherapy in stage IIIA-N2 patients with SMARCA4-deficient lung adenocarcinoma: a case report.AME case reports · 2026Article
- FGFR Aberrations in Solid Tumors: Mechanistic Insights and Clinical Translation of Targeted Therapies.Cancers · 2025Review
- Review
- SMARCA2 is an essential and potent cofactor for a specific subset of the glucocorticoid response in A549 cells.bioRxiv : the preprint server for biology · 2025Article
- Review
- 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
- Enhancer reprogramming: critical roles in cancer and promising therapeutic strategies.Cell death discovery · 2025Review
- Significance of ARID1A in neuroblastoma onset mechanism.Frontiers in oncology · 2025Review
Corrections and comments
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Authors and funding
13 authors.
Funding
Abstract
Genomic studies have identified frequent mutations in subunits of the SWI/SNF (switch/sucrose non-fermenting) chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer (NSCLC). Genetic evidence indicates that the paralog SMARCA2 is synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. Here, we utilized structure-activity relationship (SAR) studies to develop YD23, a potent and selective proteolysis targeting chimera (PROTAC) targeting SMARCA2. Mechanistically, we show that SMARCA2 degradation induces reprogramming of the enhancer landscape in SMARCA4-mutant cells with loss of chromatin accessibility at enhancers of genes involved in cell proliferation. Furthermore, we identified YAP/TEADas key partners to SMARCA2 in driving growth of SMARCA4-mutant cells. Finally, we show that YD23 has potent tumor growth inhibitory activity in SMARCA4-mutant xenografts. These findings provide the mechanistic basis for development of SMARCA2 degraders as synthetic lethal therapeutics against SMARCA4-mutant lung cancers.
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Registered trials
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