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Inhibition of DNA glycosylases in development of cancer therapeutics

Published

Author(s)

M Miral Dizdar, Pawel Jaruga, Erdem Coskun, Marcus J. Calkins, Nathan Donley, Dorjbal Dorjsuren, Anton Simeonov, Amanda K. McCullough, R S. Lloyd, Ajit Jadhav

Abstract

In cancer therapy, the efficacy of therapeutic agents may be influenced by increased DNA repair capacity. This may be due to overexpression of DNA repair proteins that repair therapy-induced DNA lesions in tumors before they become toxic. Inhibition of DNA repair is a logical approach to enhance the efficacy of DNA damage-based therapy of cancer. Thus, DNA repair pathways have become promising targets for novel cancer treatments. There are intense efforts worldwide to develop drugs that inhibit the activities of DNA repair proteins in tumors. Although most targeted proteins belong to the base excision repair pathway, the development of inhibitors has been lagging for DNA glycosylases. To discover inhibitors of human DNA glycosylases NEIL1, OGG1 and NTH1, we developed a high-throughput assay to detect both glycosylase and lyase activities of these proteins. From a screen of ∼400,000 compounds, several purine analogs for NEIL1 and NTH1, and hydrazyde derivatives for OGG1 were identified as potent inhibitors. We then applied gas chromatography/tandem mass spectrometry to determine the inhibition of excision of these proteins’ known substrates. Four purine analogs were found to be potent inhibitors of NEIL1 by mainly blocking the glycosylase activity. Two of them also efficiently inhibited NTH1. However, OGG1 was not inhibited by these compounds. Five hydrazyde derivatives inhibited OGG1, but not NEIL1 or NTH1, by blocking the Schiff base formation, thus inhibiting the combined glycosylase/lyase activity. Taken together, our work may serve as the foundation for the discovery of inhibitors of human DNA glycosylases as drugs in cancer therapy.
Proceedings Title
EUROTOX 2016 Congress, Seville, Spain
Conference Dates
September 4-7, 2016
Conference Location
Seville
Conference Title
EUROTOX 2016 Congress

Citation

, M. , Jaruga, P. , Coskun, E. , Calkins, M. , Donley, N. , Dorjsuren, D. , Simeonov, A. , McCullough, A. , Lloyd, R. and Jadhav, A. (2016), Inhibition of DNA glycosylases in development of cancer therapeutics, EUROTOX 2016 Congress, Seville, Spain, Seville, -1 (Accessed April 25, 2024)
Created September 4, 2016, Updated January 27, 2020