The MRE11-RAD50-NBS1 complex plays key roles in preserving genomic integrity by either acting as a DNA damage sensor or directly promoting DNA repair through the exo- and endonuclease activities of the MRE11 subunit. Nuclease MRE11 is of interest as a potential drug target in oncology due to its role in DNA repair and its association with the molecular pathology of cancer. This proposed interdisciplinary medicinal chemistry project is based on the organic synthesis of analogues of our recently identified compound, which is significantly more potent than the few heretofore known weak and non-selective inhibitors of MRE11. Biological evaluation of the analogs’ MRE11 inhibitory activity will result in the structure-activity relationship coverage of the chemical space around the central pharmacophore and possibly in identification of more pharmacologically robust substances. The development of novel efficient inhibitors of MRE11 will be complementary to the validation of MRE11 synthetic lethal partners (FEN1 and BRCA2), an emerging strategy for targeted therapies in cancer research.

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