Small-molecule Effectors of DNA Repair Proteins: Applications for Development of Cancer Therapeutics and Research
Cancer
Abstract
A ubiquitous aspect of cellular life is the need to repair the many deleterious DNA lesions that arise due to environmental damage and as byproducts of normal cellular metabolism. The same DNA repair processes, which are critical for life, are also employed by cancer cells in their resistance to radiation and DNA-damaging therapies. Inhibition of DNA repair or entrapment of the toxic DNA repair intermediates with the help of small molecules has both potential therapeutic and research utility. Although many proteins that maintain genome integrity and repair DNA damage appear to be attractive targets, they lack well-defined small-molecule binding determinants and clear structure–activity relationships. This article summarizes a number of studies that have led to the identification of small-molecule drug lead compounds, which may also be useful in dissecting complex DNA repair networks. Systems that are particularly noteworthy are inhibition of PARP1, as it is a paradigm case for achieving successful clinical applications, and the emerging targets RAD51 recombinase, RAD52 DNA repair protein, MRE11 nuclease, and WRN DNA helicase.
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