July 21, 2015

Journal of Biomolecular Screening Vol 20(7) 842-848

Discovery of SIRT3 Inhibitors Using SAMDI Mass Spectrometry

Kaushal Patel1, John Sherrill1, Milan Mrksich2, and Michael D. Scholle1

1SAMDI Tech, Inc., Chicago, IL, USA
2Department of Biomedical Engineering, Department of Chemistry, and Department of Cell and Molecular Biology, Northwestern University, Evanston, IL, USA

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 (GYKAcRGC). 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 IC50 of 700 nM with >100-fold selectivity for SIRT3 over SIRT1. View PDF

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