ArticleNature communications2020
Identification of phenothiazine derivatives as UHM-binding inhibitors of early spliceosome assembly.
Article in Nature communications, 2020. 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, 31 citations in OpenAlex.
- The cellular landscape of druggable RNA-binding proteins.Nature reviews. Drug discovery · 2026Review
- Exploitation of host U2AF1 and U2AF2 splicing factors facilitates mosquito-borne orthoflavivirus infection across species.Nucleic acids research · 2026Article
- Integrative CRISPR Screening and RNA Analyses Discover an Essential Role for PUF60 Interactions with 3' Splice Sites in Cancer Progression.Cancer research · 2026Article
- Targeting RNA binding proteins with small-molecule inhibitors: Advances, challenges, and therapeutic opportunities.Acta pharmaceutica Sinica. B · 2026Review
- The Function of Poly (U) Binding Splicing Factor 60 (PUF60) in Disease Regulation.Anti-cancer agents in medicinal chemistry · 2026Review
- RNA Splicing as a Therapeutic Target in Cancer.Annual review of pharmacology and toxicology · 2026Review
- An inhibitor of UHM splicing factors exerts anti-leukemic activity by altering cell cycle progression and reducing lysosome acidification.Cellular signalling · 2025Article
- Targeting RNA splicing modulation: new perspectives for anticancer strategy?Journal of experimental & clinical cancer research : CR · 2025Review
- Aberrant pre-mRNA processing in cancer.The Journal of experimental medicine · 2024Review
- Small molecules modulating RNA splicing: a review of targets and future perspectives.RSC medicinal chemistry · 2024Review
- Therapeutic Targeting of RNA Splicing in Cancer.Genes · 2023Review
- Profiling the Binding Activities of Peptides and Inhibitors to the U2 Auxiliary Factor Homology Motif (UHM) Domains.ACS medicinal chemistry letters · 2023Article
- Targeting splicing factors for cancer therapy.RNA (New York, N.Y.) · 2023Article
- Using the structural diversity of RNA: protein interfaces to selectively target RNA with small molecules in cells: methods and perspectives.Frontiers in molecular biosciences · 2023Review
- Dysregulation and therapeutic targeting of RNA splicing in cancer.Nature cancer · 2022Review
- Review
- A synthetic small molecule stalls pre-mRNA splicing by promoting an early-stage U2AF2-RNA complex.Cell chemical biology · 2021Article
- Review
- Therapeutic Modulation of RNA Splicing in Malignant and Non-Malignant Disease.Trends in molecular medicine · 2021Review
- Biology of the mRNA Splicing Machinery and Its Dysregulation in Cancer Providing Therapeutic Opportunities.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
15 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Interactions between U2AF homology motifs (UHMs) and U2AF ligand motifs (ULMs) play a crucial role in early spliceosome assembly in eukaryotic gene regulation. UHM-ULM interactions mediate heterodimerization of the constitutive splicing factors U2AF65 and U2AF35 and between other splicing factors that regulate spliceosome assembly at the 3' splice site, where UHM domains of alternative splicing factors, such as SPF45 and PUF60, contribute to alternative splicing regulation. Here, we performed high-throughput screening using fluorescence polarization assays with hit validation by NMR and identified phenothiazines as general inhibitors of UHM-ULM interactions. NMR studies show that these compounds occupy the tryptophan binding pocket of UHM domains. Co-crystal structures of the inhibitors with the PUF60 UHM domain and medicinal chemistry provide structure-activity-relationships and reveal functional groups important for binding. These inhibitors inhibit early spliceosome assembly on pre-mRNA substrates in vitro. Our data show that spliceosome assembly can be inhibited by targeting UHM-ULM interactions by small molecules, thus extending the toolkit of splicing modulators for structural and biochemical studies of the spliceosome and splicing regulation.
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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.