Discovery of SIRT3 Inhibitors Using SAMDI Mass Spectrometry.

Abstract

Lysine acetylation plays a critical role in cellular regulation and is implicated in human disease. Sirtuin deacetylases remove acetyl groups from modified lysine residues, and sirtuin 3 (SIRT3) has been identified as a target for cancer therapeutics. Robust and high-throughput screening methods for these targets will be important to the development of therapeutics. This article describes the use of self-assembled monolayer desorption/ionization mass spectrometry, or SAMDI-MS-a label-free drug discovery tool--to characterize SIRT3 activity and discover inhibitors. SAMDI-MS was used to analyze a peptide array having 361 distinct acetylated peptides to identify an active SIRT3 substrate (GYK(Ac)RGC). This peptide was used in a screen of 100,000 small molecules to identify inhibitors of SIRT3. A total of 306 SIRT3 inhibitors were identified, with one compound, SDX-437, having an IC(50) of 700 nM with >100-fold selectivity for SIRT3 over SIRT1.

• Authors: Kaushal Patel, John Sherrill, Milan Mrksich, Michael D Scholle
• Journal: Journal of biomolecular screening (J Biomol Screen) Vol. 20 Issue 7 Pg. 842-8 (Aug 2015) ISSN: 1552-454X [Electronic] United States
• PMID: 26024947 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 Society for Laboratory Automation and Screening.

Chemical References

• Histone Deacetylase Inhibitors
• Sirtuin 3

Topics

• Acetylation
• Drug Discovery (methods)
• Enzyme Activation (drug effects)
• High-Throughput Screening Assays
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Mass Spectrometry (methods)
• Sirtuin 3 (antagonists & inhibitors)