ArticleCell chemical biology2021
A synthetic small molecule stalls pre-mRNA splicing by promoting an early-stage U2AF2-RNA complex.
Article in Cell chemical biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 37 citations in OpenAlex.
- The cellular landscape of druggable RNA-binding proteins.Nature reviews. Drug discovery · 2026Review
- Deconvoluting the multi-faceted roles of alternative splicing events in cancer: From underlying mechanisms to innovative therapeutics.Acta pharmaceutica Sinica. B · 2026Review
- Combining cutting edge computational and experimental methods for targeting KRAS mutations in non-small cell lung cancer.Expert opinion on drug discovery · 2026Review
- Multiscale analysis and optimal glioma therapeutic candidate discovery using the CANDO platform.Journal of cheminformatics · 2026Article
- Targeting RNA binding proteins with small-molecule inhibitors: Advances, challenges, and therapeutic opportunities.Acta pharmaceutica Sinica. B · 2026Review
- SF3B1 Phosphorylation Prompts U2AF2 Dissociation for Widespread Control of pre-mRNA Splicing.bioRxiv : the preprint server for biology · 2026Article
- RNA Splicing as a Therapeutic Target in Cancer.Annual review of pharmacology and toxicology · 2026Review
- Genome-wide modulation of alternative splicing by a predicted alpha helix in U2AF2.Nucleic acids research · 2025Article
- Strategies for robust, accurate, and generalizable benchmarking of drug discovery platforms.Bioinformatics (Oxford, England) · 2025Article
- Strategies for robust, accurate, and generalizable benchmarking of drug discovery platforms.bioRxiv : the preprint server for biology · 2025Article
- Targeting RNA splicing modulation: new perspectives for anticancer strategy?Journal of experimental & clinical cancer research : CR · 2025Review
- Steering research on mRNA splicing in cancer towards clinical translation.Nature reviews. Cancer · 2024Review
- Aberrant pre-mRNA processing in cancer.The Journal of experimental medicine · 2024Review
- Comprehensive Analyses of the Effects of the Small-Molecule Inhibitor of the UHM Domain in the Splicing FactorResearch square · 2024Article
- Small molecules modulating RNA splicing: a review of targets and future perspectives.RSC medicinal chemistry · 2024Review
- R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription-Replication Conflicts.Cancer research · 2024Article
- U2AF1 in various neoplastic diseases and relevant targeted therapies for malignant cancers with complex mutations (Review).Oncology reports · 2024Review
- Rationally designed stapled peptides allosterically inhibit PTBP1-RNA-binding.Chemical science · 2023Article
- Therapeutic Targeting of RNA Splicing in Cancer.Genes · 2023Review
- A presumed missense variant in the U2AF2 gene causes exon skipping in neurodevelopmental diseases.Journal of human genetics · 2023Review
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Authors and funding
15 authors at 6 institutions in 1 country.
Funding
Abstract
Dysregulated pre-mRNA splicing is an emerging Achilles heel of cancers and myelodysplasias. To expand the currently limited portfolio of small-molecule drug leads, we screened for chemical modulators of the U2AF complex, which nucleates spliceosome assembly and is mutated in myelodysplasias. A hit compound specifically enhances RNA binding by a U2AF2 subunit. Remarkably, the compound inhibits splicing of representative substrates and stalls spliceosome assembly at the stage of U2AF function. Computational docking, together with structure-guided mutagenesis, indicates that the compound bridges the tandem U2AF2 RNA recognition motifs via hydrophobic and electrostatic moieties. Cells expressing a cancer-associated U2AF1 mutant are preferentially killed by treatment with the compound. Altogether, our results highlight the potential of trapping early spliceosome assembly as an effective pharmacological means to manipulate pre-mRNA splicing. By extension, we suggest that stabilizing assembly intermediates may offer a useful approach for small-molecule inhibition of macromolecular machines.
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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.