ArticlePloS one2012
Largazole and its derivatives selectively inhibit ubiquitin activating enzyme (e1).
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 65 citations in OpenAlex.
- Multidrug-resistant tuberculosis: a comprehensive review of pathogenesis, drug resistance, current treatment and future prospects.Archives of microbiology · 2026Review
- Progress in discovery and development of natural inhibitors of histone deacetylases (HDACs) as anti-cancer agents.Naunyn-Schmiedeberg's archives of pharmacology · 2024Review
- Marine Cyanobacteria as Sources of Lead Anticancer Compounds: A Review of Families of Metabolites with Cytotoxic, Antiproliferative, and Antineoplastic Effects.Molecules (Basel, Switzerland) · 2022Review
- A series of xanthenes inhibiting Rad6 function and Rad6-Rad18 interaction in the PCNA ubiquitination cascade.iScience · 2022Article
- Article
- Pharmacological Modulation of Ubiquitin-Proteasome Pathways in Oncogenic Signaling.International journal of molecular sciences · 2021Review
- Natural compounds in the regulation of proteostatic pathways: An invincible artillery against stress, ageing, and diseases.Acta pharmaceutica Sinica. B · 2021Review
- Natural Cyclopeptides as Anticancer Agents in the Last 20 Years.International journal of molecular sciences · 2021Review
- Mode of inhibitory binding of epigallocatechin gallate to the ubiquitin-activating enzyme Uba1RSC advances · 2021Article
- Cyanobacteria as Natural Therapeutics and Pharmaceutical Potential: Role in Antitumor Activity and as Nanovectors.Molecules (Basel, Switzerland) · 2021Review
- Repurposing old drugs as new inhibitors of the ubiquitin-proteasome pathway for cancer treatment.Seminars in cancer biology · 2021Review
- Marine Cyanobacteria: A Source of Lead Compounds and their Clinically-Relevant Molecular Targets.Molecules (Basel, Switzerland) · 2020Review
- Ubiquitination and the Proteasome as Drug Targets in Trypanosomatid Diseases.Frontiers in chemistry · 2020Review
- Inhibition of the Ubiquitin-Activating Enzyme UBA1 Suppresses Diet-Induced Atherosclerosis in Apolipoprotein E-Knockout Mice.Journal of immunology research · 2020Article
- Multilevel structure-activity profiling reveals multiple green tea compound families that each modulate ubiquitin-activating enzyme and ubiquitination by a distinct mechanism.Scientific reports · 2019Article
- Natural Products from Cyanobacteria: Focus on Beneficial Activities.Marine drugs · 2019Review
- A patent review of the ubiquitin ligase system: 2015-2018.Expert opinion on therapeutic patents · 2018Review
- Clogging the Ubiquitin-Proteasome Machinery with Marine Natural Products: Last Decade Update.Marine drugs · 2018Review
- 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
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Protein ubiquitination plays an important role in the regulation of almost every aspect of eukaryotic cellular function; therefore, its destabilization is often observed in most human diseases and cancers. Consequently, developing inhibitors of the ubiquitination system for the treatment of cancer has been a recent area of interest. Currently, only a few classes of compounds have been discovered to inhibit the ubiquitin-activating enzyme (E1) and only one class is relatively selective in E1 inhibition in cells. We now report that Largazole and its ester and ketone analogs selectively inhibit ubiquitin conjugation to p27(Kip1) and TRF1 in vitro. The inhibitory activity of these small molecules on ubiquitin conjugation has been traced to their inhibition of the ubiquitin E1 enzyme. To further dissect the mechanism of E1 inhibition, we analyzed the effects of these inhibitors on each of the two steps of E1 activation. We show that Largazole and its derivatives specifically inhibit the adenylation step of the E1 reaction while having no effect on thioester bond formation between ubiquitin and E1. E1 inhibition appears to be specific to human E1 as Largazole ketone fails to inhibit the activation of Uba1p, a homolog of E1 in Schizosaccharomyces pombe. Moreover, Largazole analogs do not significantly inhibit SUMO E1. Thus, Largazole and select analogs are a novel class of ubiquitin E1 inhibitors and valuable tools for studying ubiquitination in vitro. This class of compounds could be further developed and potentially be a useful tool in cells.
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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.