ArticleACS medicinal chemistry letters2014
Modulation of Activity Profiles for Largazole-Based HDAC Inhibitors through Alteration of Prodrug Properties.
Article in ACS medicinal chemistry letters, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Small molecular weight epigenetic inhibitors modulate the extracellular matrix during pancreatic acinar ductal metaplasia.Biochemical and biophysical research communications · 2024Article
- Epigenetic small-molecule screen for inhibition and reversal of acinar ductal metaplasia in mouse pancreatic organoids.Frontiers in pharmacology · 2024Article
- Classification models and SAR analysis on HDAC1 inhibitors using machine learning methods.Molecular diversity · 2023Article
- Naturally occurring small molecule compounds that target histone deacetylases and their potential applications in cancer therapy.The Journal of antibiotics · 2021Review
- Largazole is a Brain-Penetrant Class I HDAC Inhibitor with Extended Applicability to Glioblastoma and CNS Diseases.ACS chemical neuroscience · 2020Article
- Review
- Selective Inhibition of HDAC1 by Macrocyclic Polypeptide for the Treatment of Glioblastoma: A Binding Mechanistic Analysis Based on Molecular Dynamics.Frontiers in molecular biosciences · 2020Article
- Article
- Histone Deacetylase Inhibition Sensitizes PD1 Blockade-Resistant B-cell Lymphomas.Cancer immunology research · 2019Article
- Therapeutic Properties and Biological Benefits of Marine-Derived Anticancer Peptides.International journal of molecular sciences · 2018Review
- Process Development and Scale-up Total Synthesis of Largazole, a Potent Class I Histone Deacetylase Inhibitor.Organic process research & development · 2018Article
- Synthesis and biological evaluation of largazole zinc-binding group analogs.Bioorganic & medicinal chemistry · 2017Article
- Peptides, Peptidomimetics, and Polypeptides from Marine Sources: A Wealth of Natural Sources for Pharmaceutical Applications.Marine drugs · 2017Review
- Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue.Journal of medicinal chemistry · 2016Article
- Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents.Molecules (Basel, Switzerland) · 2015Review
- Biological targets and mechanisms of action of natural products from marine cyanobacteria.Natural product reports · 2015Review
- An overview of naturally occurring histone deacetylase inhibitors.Current topics in medicinal chemistry · 2015Review
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Authors and funding
9 authors.
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Abstract
Largazole is a potent and class I-selective histone deacetylase (HDAC) inhibitor purified from marine cyanobacteria and was demonstrated to possess antitumor activity. Largazole employs a unique prodrug strategy, via a thioester moiety, to liberate the bioactive species largazole thiol. Here we report alternate prodrug strategies to modulate the pharmacokinetic and pharmacodynamics profiles of new largazole-based compounds. The in vitro effects of largazole analogues on cancer cell proliferation and enzymatic activities of purified HDACs were comparable to the natural product. However, in vitro and in vivo histone hyperacetylation in HCT116 cells and implanted tumors, respectively, showed differences, particularly in the onset of action and oral bioavailability. These results indicate that, by employing a different approach to disguise the "warhead" moiety, the functional consequence of these prodrugs can be significantly modulated. Our data corroborate the role of the pharmacokinetic properties of this class of compounds to elicit the desired and timely functional response.
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