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Application of mass spectrometry in the discovery of small molecule inhibitors of DNA repair proteins as potential anticancer drugs

Published

Author(s)

M Miral Dizdar

Abstract

Most therapeutic agents kill tumor cells by damaging DNA. Evidence shows that cancer cells increase their capacity to repair DNA by overexpressing DNA repair proteins. Increased DNA repair that may remove DNA lesions before they become toxic to cancer cells is a major mechanism for the development of resistance to therapy. DNA repair proteins constitute targets for inhibitors to overcome the therapy resistance. Inhibition of DNA repair proteins may help selectively kill cancer cells in combination therapy or monotherapy. Among DNA repair proteins, DNA glycosylases remove modified DNA bases in the first step of the base excision repair mechanism, paving the way for other proteins to fully repair DNA. We planned experiments to discover small molecule inhibitors of human DNA glycosylases NEIL1, OGG1 and NTH1. First, a fluorescence-based assay was developed to detect both glycosylase and lyase activities of these proteins. From a primary screen of ∼400,000 compunds, a number of inhibitors were identified. We applied GC-MS/MS with isotope dilution to determine the inhibition of NEIL1, OGG1 and NTH1 by identifying and quantifying the excised levels of their substrates. Four purine analogs were found to be potent inhibitors of the excision of NEIL1 substrates. Three of the four NEIL1 inhibitors also inhibited the exicision of NTH1 substrates, but not those of OGG1. Five other inhibitors were found to be potent inhibitors of the excision of OGG1 substrates; however, they displayed no inhibition of NEIL1 and NTH1 activities. Overall, this work forms the foundation for future drug discovery for DNA glycosylases.
Conference Dates
July 20-22, 2016
Conference Location
Chicago, IL
Conference Title
2nd International Conference on Current Trends in Mass Spectrometry

Keywords

GC-MS/MS, DNA glycosylases, inhibitors, cancer therapy

Citation

, M. (2016), Application of mass spectrometry in the discovery of small molecule inhibitors of DNA repair proteins as potential anticancer drugs, 2nd International Conference on Current Trends in Mass Spectrometry, Chicago, IL (Accessed July 21, 2024)

Issues

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Created July 20, 2016, Updated February 19, 2020