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Small molecule inhibitors of DNA repair nuclease activities of APE1

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Abstract

APE1 is a multifunctional protein that possesses several nuclease activities, including the ability to incise at apurinic/apyrimidinic (AP) sites in DNA or RNA, to excise 3′-blocking termini from DNA ends, and to cleave at certain oxidized base lesions in DNA. Pre-clinical and clinical data indicate a role for APE1 in the pathogenesis of cancer and in resistance to DNA-interactive drugs, particularly monofunctional alkylators and antimetabolites. In an effort to improve the efficacy of therapeutic compounds, such as temozolomide, groups have begun to develop high-throughput screening assays and to identify small molecule inhibitors against APE1 repair nuclease activities. It is envisioned that such inhibitors will be used in combinatorial treatment paradigms to enhance the efficacy of DNA-interactive drugs that introduce relevant cytotoxic DNA lesions. In this review, we summarize the current state of the efforts to design potent and selective inhibitors against APE1 AP site incision activity.

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Acknowledgments

We thank Drs. Mamta Naidu (Brookhaven National Laboratory, USA) and Srinivasan Madhusudan (University of Nottingham, UK) for sharing unpublished observations and for constructive input to the manuscript. This work was supported by the Intramural Research Program of the National Institute on Aging, NIH; the Molecular Libraries Initiative of the NIH Roadmap for Medical Research; the Intramural Research Program of National Human Genome Research Institute, NIH; and grant 1 R03 MH086444-01 to D.M.W. III.

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Wilson, D.M., Simeonov, A. Small molecule inhibitors of DNA repair nuclease activities of APE1. Cell. Mol. Life Sci. 67, 3621–3631 (2010). https://doi.org/10.1007/s00018-010-0488-2

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