ArticlePloS one2015
Novel Activities of Select NSAID R-Enantiomers against Rac1 and Cdc42 GTPases.
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 29 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
29 citing papers in PubMed, 58 citations in OpenAlex.
- Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via upregulation of P-Rex1/Rac1 signalling.Nature communications · 2026Article
- Healing dynamics and surgery in breast cancer: rethinking a timeless challenge in light of advancing therapies and technologies.Journal of translational medicine · 2026Review
- Drug-drug interactions between sex hormones and analgesics linked to thromboembolic events: an FDA adverse event reporting system analysis.Frontiers in pharmacology · 2026Article
- Targeting CDC42 Protects Mitochondrial Function through KLF2/HIF-1α/PINK1 Signaling in Acute Kidney Injury.International journal of biological sciences · 2026Article
- R-ketorolac ameliorates cancer-associated cachexia and prolongs survival of tumour-bearing mice.Journal of cachexia, sarcopenia and muscle · 2024Article
- Intraoperative Ketorolac and Outcomes after Ovarian Cancer Surgery.Journal of clinical medicine · 2024Article
- Agent-based modeling predicts RAC1 is critical for ovarian cancer metastasis.Molecular biology of the cell · 2022Article
- Organoid-on-a-chip model of human ARPKD reveals mechanosensing pathomechanisms for drug discovery.Science advances · 2022Article
- Role of Host Small GTPases in Apicomplexan Parasite Infection.Microorganisms · 2022Review
- Targeting Small GTPases and Their Prenylation in Diabetes Mellitus.Journal of medicinal chemistry · 2021Review
- Article
- Rac1, A Potential Target for Tumor Therapy.Frontiers in oncology · 2021Review
- Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases.Frontiers in cellular neuroscience · 2021Article
- Review
- Dual Actions of Ketorolac in Metastatic Ovarian Cancer.Cancers · 2019Review
- Combined inhibition of RAC1 and Bcl-2/Bcl-xL synergistically induces glioblastoma cell death through down-regulation of the Usp9X/Mcl-1 axis.Cellular oncology (Dordrecht, Netherlands) · 2019Article
- Identification of the first enantiopure Rac1-Tiam1 protein-protein interaction inhibitor and its optimized synthesisMedChemComm · 2019Article
- Druggable targets in the Rho pathway and their promise for therapeutic control of blood pressure.Pharmacology & therapeutics · 2019Review
- Review
- Targeting Rac and Cdc42 GTPases in Cancer.Cancer research · 2018Review
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
Abstract
Rho family GTPases (including Rac, Rho and Cdc42) collectively control cell proliferation, adhesion and migration and are of interest as functional therapeutic targets in numerous epithelial cancers. Based on high throughput screening of the Prestwick Chemical Library® and cheminformatics we identified the R-enantiomers of two approved drugs (naproxen and ketorolac) as inhibitors of Rac1 and Cdc42. The corresponding S-enantiomers are considered the active component in racemic drug formulations, acting as non-steroidal anti-inflammatory drugs (NSAIDs) with selective activity against cyclooxygenases. Here, we show that the S-enantiomers of naproxen and ketorolac are inactive against the GTPases. Additionally, more than twenty other NSAIDs lacked inhibitory action against the GTPases, establishing the selectivity of the two identified NSAIDs. R-naproxen was first identified as a lead compound and tested in parallel with its S-enantiomer and the non-chiral 6-methoxy-naphthalene acetic acid (active metabolite of nabumetone, another NSAID) as a structural series. Cheminformatics-based substructure analyses-using the rotationally constrained carboxylate in R-naproxen-led to identification of racemic [R/S] ketorolac as a suitable FDA-approved candidate. Cell based measurement of GTPase activity (in animal and human cell lines) demonstrated that the R-enantiomers specifically inhibit epidermal growth factor stimulated Rac1 and Cdc42 activation. The GTPase inhibitory effects of the R-enantiomers in cells largely mimic those of established Rac1 (NSC23766) and Cdc42 (CID2950007/ML141) specific inhibitors. Docking predicts that rotational constraints position the carboxylate moieties of the R-enantiomers to preferentially coordinate the magnesium ion, thereby destabilizing nucleotide binding to Rac1 and Cdc42. The S-enantiomers can be docked but are less favorably positioned in proximity to the magnesium. R-naproxen and R-ketorolac have potential for rapid translation and efficacy in the treatment of several epithelial cancer types on account of established human toxicity profiles and novel activities against Rho-family GTPases.
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What OpenQuestion holds
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.