Selective Inhibition of DNA Polymerase β by a Covalent Inhibitor.

ABSTRACT: DNA polymerase β (Pol β) plays a vital role in DNA repair and has been closely linked to cancer. Selective inhibitors of this enzyme are lacking. Inspired by DNA lesions produced by antitumor agents that inactivate Pol β, we have undertaken the development of covalent small-molecule inhibitors of this enzyme. Using a two-stage process involving chemically synthesized libraries, we identified a potent irreversible inhibitor (14) of Pol β (K_I = 1.8 ± 0.45 μM, k_inact = (7.0 ± 1.0) × 10^-3 s^-1). Inhibitor 14 selectively inactivates Pol β over other DNA polymerases. LC-MS/MS analysis of trypsin digests of Pol β treated with 14 identified two lysines within the polymerase binding site that are covalently modified, one

SUBMITTER: Yuhas SC 

PROVIDER: S-EPMC8284926 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature