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, gamma-radiolysis). DNA polymerase beta (Pol beta) 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 DNA damaging agents (bleomycin, MMS) to kill prostate cancer cells. The inhibitor was derived from a library of molecules whose design was driven by our demonstration that certain DNA lesions produced by cytotoxic antitumor agents irreversibly inactivate Pol beta.
For relevant publications 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)
• Synergistic Effects of an Irreversible DNA Polymerase Inhibitor and DNA Damaging Agents on HeLa Cells. Paul, R.; Banerjee, S.; Greenberg, M. M. ACS Chem. Biol. 2017, 12, 1576-1583. Correction: ACS Chem. Biol. 2018, 13, 832-832. (PMC: 5492961) (Highlighted (“Spotlight”) in Chem. Res. Toxicol. 2017, 30, 1367-1368.)