Protein Domain Specific Covalent Inhibition of Human DNA Polymerase β.

ABSTRACT: DNA polymerase β (Pol β) is a frequently overexpressed and/or mutated bifunctional repair enzyme. Pol β possesses polymerase and lyase active sites, that are employed in two steps of base excision repair. Pol β is an attractive therapeutic target for which there is a need for inhibitors. Two mechanistically inspired covalent inhibitors (1, IC₅₀ =21.0 μM; 9, IC₅₀ =18.7 μM) that modify lysine residues in different Pol β active sites are characterized. Despite modifying lysine residues in different active sites, 1 and 9 inactivate the polymerase and lyase activities of Pol β. 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 bifunc

SUBMITTER: Yuhas SC 

PROVIDER: S-EPMC8373715 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature