ArticleThe Journal of pharmacology and experimental therapeutics2009
Structure-activity relationship studies of fostriecin, cytostatin, and key analogs, with PP1, PP2A, PP5, and( beta12-beta13)-chimeras (PP1/PP2A and PP5/PP2A), provide further insight into the inhibitory actions of fostriecin family inhibitors.
Article in The Journal of pharmacology and experimental therapeutics, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 59 citations in OpenAlex.
- Covalent warhead assembly in fostriecin biosynthesis involves malonylation-lactonisation by a bifunctional thioesterase and enzymatic demalonylation.Nature communications · 2026Article
- Diarrhetic Shellfish Poisoning Toxins: Current Insights into Toxicity, Mechanisms, and Ecological Impacts.Marine drugs · 2025Review
- Concise Synthesis of Fostriecin and Analogs through Late-Stage Chemoenzymatic Installation of Their Key Pharmacophores.Journal of the American Chemical Society · 2025Article
- Loss of serine/threonine protein phosphatase 6 severely impairs sexual stage development in malaria parasite Plasmodium berghei.PLoS pathogens · 2025Article
- Peroxide-Mediated Release of Organophosphates from Boron-Containing Phosphotriesters: A New Class of Organophosphate Prodrugs.Organic letters · 2023Article
- Discovery of the allosteric inhibitor from actinomyces metabolites to target EGFRScientific reports · 2023Article
- PP4 inhibition sensitizes ovarian cancer to NK cell-mediated cytotoxicity via STAT1 activation and inflammatory signaling.Journal for immunotherapy of cancer · 2022Article
- Strategies for Solubility and Bioavailability Enhancement and Toxicity Reduction of Norcantharidin.Molecules (Basel, Switzerland) · 2022Review
- Review
- The potent protein phosphatase 2A inhibitors aminocytostatins: new derivatives of cytostatin.The Journal of antibiotics · 2021Article
- YAP1 and its fusion proteins in cancer initiation, progression and therapeutic resistance.Developmental biology · 2021Review
- Catalytic ChemoselectiveACS central science · 2020Article
- The Antitumor Drug LB-100 Is a Catalytic Inhibitor of Protein Phosphatase 2A (PPP2CA) and 5 (PPP5C) Coordinating with the Active-Site Catalytic Metals in PPP5C.Molecular cancer therapeutics · 2019Article
- Inhibitors of Serine/Threonine Protein Phosphatases: Biochemical and Structural Studies Provide Insight for Further Development.Current medicinal chemistry · 2019Review
- PP1:Tautomycetin Complex Reveals a Path toward the Development of PP1-Specific Inhibitors.Journal of the American Chemical Society · 2017Article
- The Difference a Single Atom Can Make: Synthesis and Design at the Chemistry-Biology Interface.The Journal of organic chemistry · 2017Article
- An Ultra-High-Throughput Screen for Catalytic Inhibitors of Serine/Threonine Protein Phosphatases Types 1 and 5 (PP1C and PP5C).SLAS discovery : advancing life sciences R & D · 2017Article
- Synthetic Strategies Employed for the Construction of Fostriecin and Related Natural Products.Chemical reviews · 2016Review
- Structure-Activity Relationship Studies Using Natural and Synthetic Okadaic Acid/Dinophysistoxin Toxins.Marine drugs · 2016Article
- Crystal structures and mutagenesis of PPP-family ser/thr protein phosphatases elucidate the selectivity of cantharidin and novel norcantharidin-based inhibitors of PP5C.Biochemical pharmacology · 2016Article
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Fostriecin and cytostatin are structurally related natural inhibitors of serine/threonine phosphatases, with promising antitumor activity. The total synthesis of these antitumor agents has enabled the production of structural analogs, which are useful to explore the biological significance of features contained in the parent compounds. Here, the inhibitory activity of fostriecin, cytostatin, and 10 key structural analogs were tested in side-by-side phosphatase assays to further characterize their inhibitory activity against PP1c (Ser/Thr protein phosphatase 1 catalytic subunit), PP2Ac (Ser/Thr protein phosphatase 2A catalytic subunit), PP5c (Ser/Thr protein phosphatase 5 catalytic subunit), and chimeras of PP1 (Ser/Thr protein phosphatase 1) and PP5 (Ser/Thr protein phosphatase 5), in which key residues predicted for inhibitor contact with PP2A (Ser/Thr protein phosphatase 2A) were introduced into PP1 and PP5 using site-directed mutagenesis. The data confirm the importance of the C9-phosphate and C11-alcohol for general inhibition and further demonstrate the importance of a predicted C3 interaction with a unique cysteine (Cys(269)) in the beta12-beta13 loop of PP2A. The data also indicate that additional features beyond the unsaturated lactone contribute to inhibitory potency and selectivity. Notably, a derivative of fostriecin lacking the entire lactone subunit demonstrated marked potency and selectivity for PP2A, while having substantially reduced and similar activity against PP1 and PP1/PP2A- PP5/PP2A-chimeras that have greatly increased sensitivity to both fostriecin and cytostatin. This suggests that other features [e.g., the (Z,Z,E)-triene] also contribute to inhibitory selectivity. When considered together with previous data, these studies suggest that, despite the high structural conservation of the catalytic site in PP1, PP2A and PP5, the development of highly selective catalytic inhibitors should be feasible.
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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.