ArticlePloS one2015
Inhibitors of CLK protein kinases suppress cell growth and induce apoptosis by modulating pre-mRNA splicing.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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Who cites it
70 citing papers in PubMed, 120 citations in OpenAlex.
- The periphery of nuclear speckles defines a spatially and temporally regulated compartment of long-lived intron-retained RNAs that resolves during mitosis.Nature cell biology · 2026Article
- Alternative Splicing in Cyclin-Dependent Kinase 4/6 Inhibitor Resistance in Estrogen Receptor-Positive Breast Cancer.Drug development research · 2026Review
- Nuclear speckle dynamics are controlled by polyphosphate inhibition of CLK proteins.Nucleic acids research · 2026Article
- Decoding SR protein regulation: kinases, phosphatases, and therapeutic targeting strategies.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- More than CLK bait? Rogocekib for MDS and AML.Blood advances · 2026Article
- RNA Splicing as a Therapeutic Target in Cancer.Annual review of pharmacology and toxicology · 2026Review
- SM08502-Mediated β-Catenin Repression Synergizes with Olaparib to Inhibit Tumor Progression.Cancer research communications · 2025Article
- Discovery of Rogocekib (CTX-712): A Potent and Selective CLK Inhibitor for Cancer Treatment.ACS medicinal chemistry letters · 2025Article
- Neuronal Death and Biomolecular Condensates: Are There Any New Treatment Options for Alzheimer's Disease?Cells · 2025Review
- Identification and Biological Evaluation of a Novel CLK4 Inhibitor Targeting Alternative Splicing in Pancreatic Cancer Using Structure-Based Virtual Screening.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Article
- Boronic Acid-Containing 3Pharmaceuticals (Basel, Switzerland) · 2024Article
- In silico identification of a novel Cdc2-like kinase 2 (CLK2) inhibitor in triple negative breast cancer.Protein science : a publication of the Protein Society · 2024Article
- 2-Desaza-annomontine (C81) impedes angiogenesis through reduced VEGFR2 expression derived from inhibition of CDC2-like kinases.Angiogenesis · 2024Article
- Development of 5-hydroxybenzothiophene derivatives as multi-kinase inhibitors with potential anti-cancer activity.Future medicinal chemistry · 2024Article
- Pharmacological inhibition of CLK2 activates YAP by promoting alternative splicing of AMOTL2.eLife · 2023Article
- Role of epithelial splicing regulatory protein 1 in cancer progression.Cancer cell international · 2023Review
- Alternative RNA Splicing in the Retina: Insights and Perspectives.Cold Spring Harbor perspectives in medicine · 2023Review
- Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders.FEBS letters · 2023Review
- Cdc2-like kinases: structure, biological function, and therapeutic targets for diseases.Signal transduction and targeted therapy · 2023Review
10 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Accumulating evidence has demonstrated the importance of alternative splicing in various physiological processes, including the development of different diseases. CDC-like kinases (CLKs) and serine-arginine protein kinases (SRPKs) are components of the splicing machinery that are crucial for exon selection. The discovery of small molecule inhibitors against these kinases is of significant value, not only to delineate the molecular mechanisms of splicing, but also to identify potential therapeutic opportunities. Here we describe a series of small molecules that inhibit CLKs and SRPKs and thereby modulate pre-mRNA splicing. Treatment with these small molecules (Cpd-1, Cpd-2, or Cpd-3) significantly reduced the levels of endogenous phosphorylated SR proteins and caused enlargement of nuclear speckles in MDA-MB-468 cells. Additionally, the compounds resulted in splicing alterations of RPS6KB1 (S6K), and subsequent depletion of S6K protein. Interestingly, the activity of compounds selective for CLKs was well correlated with the activity for modulating S6K splicing as well as growth inhibition of cancer cells. A comprehensive mRNA sequencing approach revealed that the inhibitors induced splicing alterations and protein depletion for multiple genes, including those involved in growth and survival pathways such as S6K, EGFR, EIF3D, and PARP. Fluorescence pulse-chase labeling analyses demonstrated that isoforms with premature termination codons generated after treatment with the CLK inhibitors were degraded much faster than canonical mRNAs. Taken together, these results suggest that CLK inhibitors exhibit growth suppression and apoptosis induction through splicing alterations in genes involved in growth and survival. These small molecule inhibitors may be valuable tools for elucidating the molecular machinery of splicing and for the potential development of a novel class of antitumor agents.
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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.