Inhibitors of DNA Repair Enzymes
Enzymes that repair damaged DNA are increasingly attractive as targets for anti-cancer agents. DNA repair enzyme inhibitors are potentially useful as adjuvants for modalities that target DNA (e.g. alkylating agents, -radiolysis). DNA polymerase is (Pol ) is an attractive target because it is vital to base excision repair and is overexpressed in many tumor cells. Recently, we reported on a mechanism-based irreversible inhibitor of Pol that works synergistically with an alklylating agent (MMS) to kill prostate cancer cells. The inhibitor was derived from a library of molecules whose design was driven by our demonstration that DNA lesions such as DOB irreversibly inactivate Pol.
For a relevant publication see:
• Irreversible Inhibition of DNA Polymerase by Small Molecule Mimics of a DNA Lesion. Arian, D.; Hedayati, M.; Zhou, H.; Bilis, Z.; Chen, K.; DeWeese, T. L.; Greenberg, M. M. J. Am. Chem. Soc. 2014, 136, 3176-3183. (PMC: 4047187)