Abstract

N-piperidinyl-benzimidazolone derivatives are selective inhibitors of of the base excision repair enzyme, 8-oxo Guanine DNA Glycosylase (OGG1). A compound series was established on the basis of a high-throughput screening and a hit-to-lead optimisation campaign resulted in the development of the tool compound TH5487 (IC50: 0.30 μM). The most potent inhibitor of the series TH8535 effectively decreased IC50 from the initial hit of 10 µM to 150 nM. Screening against five other DNA glycosylases (incl. APE1 and NEIL1) demonstrated TH8535's ability to selectively inhibit OGG1. TH8535 was proven to be efficient against several different cancer cell lines. Co-crystal structures of OGG1 with N-piperidinyl-benzimidazolone derived inhibitors revealed a chair-conformation adopted by the piperidinyl linker of potent inhibitors in contrast to a boat conformation observed with less potent inhibitors.