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Remodelin Is a Cryptic Assay Interference Chemotype That Does Not Inhibit NAT10-Dependent Cytidine Acetylation

  1. Author:
    Shrimp,Jonathan
    Jing,Yihang
    Thalalla Gamage,Supuni
    Nelson, Kathryn M.
    Han, Joseph
    Bryson, Keri M.
    Montgomery,David
    Thomas, Justin M.
    Nance,Kellie
    Sharma, Sunny
    Fox,Stephen
    Andresson,Thorkell
    Sinclair,Wilson
    Wu, Hong
    Allali-Hassani, Abdellah
    Senisterra, Guillermo
    Vedadi, Masoud
    Lafontaine, Denis
    Dahlin, Jayme L.
    Marmorstein, Ronen
    Walters, Michael A.
    Meier,Jordan

  2. Author Address

    Natl Canc Inst, Chem Biol Lab, Frederick, MD 21702 USA.Univ Minnesota, Minneapolis, MN 55455 USA.Univ Penn, Dept Chem, Philadelphia, PA 19104 USA.Rutgers State Univ, Dept Cell Biol & Neurosci, Piscataway, NJ 08854 USA.Leidos Biomed Res Inc, Prot Characterizat Lab, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA.Struct Genom Consortium, Toronto, ON M5G 1L7, Canada.Univ Libre Bruxelles, RNA Mol Biol, B-6041 Gosselies, Belgium.Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA.Harvard Med Sch, Boston, MA 02115 USA.Univ Penn, Perelman Sch Med, Dept Chem, Philadelphia, PA 19104 USA.Univ Penn, Perelman Sch Med, Dept Biochem & Biophys, Philadelphia, PA 19104 USA.Univ Penn, Perelman Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA.
    1. Year: 2021
    2. Date: Jun 10
  2. Journal: ACS MEDICINAL CHEMISTRY LETTERS
  3. AMER CHEMICAL SOC,
    1. 12
    2. 6
    3. Pages: 887-892
  5. Type of Article: Article
  6. ISSN: 1948-5875
  1. Abstract:

    Remodelin is a putative small molecule inhibitor of the RNA acetyltransferase NAT10 which has shown preclinical efficacy in models of the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS). Here we evaluate remodelin's assay interference characteristics and effects on NAT10-catalyzed RNA cytidine acetylation. We find the remodelin chemotype constitutes a cryptic assay interference compound, which does not react with small molecule thiols but demonstrates protein reactivity in ALARM NMR and proteome-wide affinity profiling assays. Biophysical analyses find no direct evidence for interaction of remodelin with the NAT10 acetyltransferase active site. Cellular studies verify that N4-acetylcytidine (ac4C) is a nonredundant target of NAT10 activity in human cell lines and find that this RNA modification is not affected by remodelin treatment in several orthogonal assays. These studies display the potential for remodelin's chemotype to interact with multiple protein targets in cells and indicate remodelin should not be applied as a specific chemical inhibitor of NAT10-catalyzed RNA acetylation.

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External Sources

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  2. DOI: 10.1021/acsmedchemlett.0c00193
  3. View record in Web of Science®
  4. WOS: 000662213200004

Library Notes

  1. Fiscal Year: FY2020-2021
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