Discovery of SIRT3 inhibitors using SAMDI mass spectrometry

Kaushal Patel; John Sherrill; Milan Mrksich; Michael D. Scholle

doi:10.1177/1087057115588512

Discovery of SIRT3 inhibitors using SAMDI mass spectrometry

Kaushal Patel, John Sherrill, Milan Mrksich, Michael D. Scholle^*

^*Corresponding author for this work

Biomedical Engineering

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

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_AcRGC). 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.

Original language	English (US)
Pages (from-to)	842-848
Number of pages	7
Journal	Journal of Biomolecular Screening
Volume	20
Issue number	7
DOIs	https://doi.org/10.1177/1087057115588512
State	Published - Aug 25 2015

Keywords

deacetylase
label-free
peptide array
self-assembled monolayers

ASJC Scopus subject areas

Drug Discovery
Analytical Chemistry
Molecular Medicine
Biochemistry
Biotechnology
Pharmacology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1177/1087057115588512

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title = "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 (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.",

keywords = "deacetylase, label-free, peptide array, self-assembled monolayers",

author = "Kaushal Patel and John Sherrill and Milan Mrksich and Scholle, {Michael D.}",

note = "Funding Information: This work was partially funded by Phase II SBIR award NSF10-607. Publisher Copyright: {\textcopyright} Society for Laboratory Automation and Screening.",

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AU - Patel, Kaushal

AU - Sherrill, John

AU - Mrksich, Milan

AU - Scholle, Michael D.

N1 - Funding Information: This work was partially funded by Phase II SBIR award NSF10-607. Publisher Copyright: © Society for Laboratory Automation and Screening.

PY - 2015/8/25

Y1 - 2015/8/25

N2 - 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.

AB - 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.

KW - deacetylase

KW - label-free

KW - peptide array

KW - self-assembled monolayers

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Discovery of SIRT3 inhibitors using SAMDI mass spectrometry

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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