Protein Domain Specific Covalent Inhibition of Human DNA Polymerase β

DNA polymerase beta (Pol beta) is a frequently overexpressed and/or mutated bifunctional repair enzyme. Pol beta possesses polymerase and lyase active sites, that are employed in two steps of base excision repair. Pol beta is an attractive therapeutic target for which there is a need for inhibitors. Two mechanistically inspired covalent inhibitors (1, IC50=21.0 mu M; 9, IC50=18.7 mu M) that modify lysine residues in different Pol beta active sites are characterized. Despite modifying lysine residues in different active sites, 1 and 9 inactivate the polymerase and lyase activities of Pol beta. Fluorescence anisotropy experiments indicate that they do so by preventing DNA binding. Inhibitors 1 and 9 provide the basis for a general approach to preparing domain selective inhibitors of bifunctional polymerases. Such molecules could prove to be useful tools for studying the role of wild type and mutant forms of Pol beta and other polymerases in DNA repair.

Automated summary

Covalent inhibitors 1 and 9 have been found to effectively inhibit the polymerase and lyase activities of Pol beta by preventing DNA binding. These inhibitors could serve as useful tools for studying the role of wild type and mutant forms of Pol beta and other polymerases in DNA repair.