ArticleAngewandte Chemie (International ed. in English)2022
Investigation of Carboxylic Acid Isosteres and Prodrugs for Inhibition of the Human SIRT5 Lysine Deacylase Enzyme.
Article in Angewandte Chemie (International ed. in English), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 32 citations in OpenAlex.
- Cycloastragenol Derivatives Improve Tyrosine Metabolism, Regulate TLR4/NF-κB/TERT Signaling Pathways, and Inhibit MPTP Induced Neuroinflammation and PD Symptoms.CNS neuroscience & therapeutics · 2026Article
- Lysine malonylation as a therapeutic target: implications for metabolic, inflammatory, and oncological disorders.Amino acids · 2025Review
- Moxibustion Alleviates Inflammation via SIRT5-mediated Post-translational Modification and Macrophage Polarization.Inflammation · 2025Article
- Advancing Covalent Ligand and Drug Discovery beyond Cysteine.Chemical reviews · 2025Review
- Quantum Evaluation of a Comprehensive Set of Carboxylic Acid Bioisosteres: Gas versus Solvated Phases.ACS omega · 2025Article
- The Role of the Sirtuin Family Histone Deacetylases in Acute Myeloid Leukemia-A Promising Road Ahead.Cancers · 2025Review
- Activation and inhibition of sirtuins: From bench to bedside.Medicinal research reviews · 2025Review
- Emerging roles of mitochondrial sirtuin SIRT5 in succinylation modification and cancer development.Frontiers in immunology · 2025Review
- Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2.Nature communications · 2024Article
- YZL-51N functions as a selective inhibitor of SIRT7 by NADiScience · 2024Article
- Deciphering functional roles of protein succinylation and glutarylation using genetic code expansion.Nature chemistry · 2024Article
- Article
- Current Trends in Sirtuin Activator and Inhibitor Development.Molecules (Basel, Switzerland) · 2024Review
- Investigating the Cytosolic Delivery of Proteins by Lipid Nanoparticles Using the Chloroalkane Penetration Assay.Biochemistry · 2024Article
- Review
- Aryl Fluorosulfate Based Inhibitors That Covalently Target the SIRT5 Lysine Deacylase.Angewandte Chemie (International ed. in English) · 2022Article
- Therapeutic Potential and Activity Modulation of the Protein Lysine Deacylase Sirtuin 5.Journal of medicinal chemistry · 2022Review
- Insights on the Modulation of SIRT5 Activity: A Challenging Balance.Molecules (Basel, Switzerland) · 2022Review
- Investigation of Carboxylic Acid Isosteres and Prodrugs for Inhibition of the Human SIRT5 Lysine Deacylase Enzyme.Angewandte Chemie (International ed. in English) · 2022Article
Corrections and comments
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Authors and funding
11 authors at 1 institution in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Sirtuin 5 (SIRT5) is a protein lysine deacylase enzyme that regulates diverse biology by hydrolyzing ϵ-N-carboxyacyllysine posttranslational modifications in the cell. Inhibition of SIRT5 has been linked to potential treatment of several cancers but potent compounds with activity in cells have been lacking. Here we developed mechanism-based inhibitors that incorporate isosteres of a carboxylic acid residue that is important for high-affinity binding to the enzyme active site. By masking of the tetrazole moiety of the most potent candidate from our initial SAR study, we achieved potent and cytoselective growth inhibition for the treatment of SIRT5-dependent leukemic cancer cell lines in culture. Thus, we provide an efficient, cellularly active small molecule that targets SIRT5, which can help elucidate its function and potential as a future drug target. This work shows that masked isosteres of carboxylic acids are viable chemical motifs for the development of inhibitors that target mitochondrial enzymes, which may have applications beyond the sirtuin field.
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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.