This technology includes a novel APEl small molecule inhibitor, which exhibits potent in vitro activity and potentiates the cytotoxicity of DNA damaging agents. APEl is the primary mammalian enzyme responsible for the removal of abasic (AP sites) in DNA and functions as part of the base excision DNA repair pathway (BER). BER is instrumental in the repair of DNA damage caused by DNA alkylating agents (e.g., many cancer chemotherapeutics). Thus, inhibition of this pathway should potentiate the cytotoxicity of such compounds. Preclinical and clinical data confirm that APEl is a valid anticancer drug target, with APEI being overexpressed in cancer cells compared to normal cells. This approach has been further validated by the success in clinical trials of another BER pathway inhibitor (PARP inhibitors), either in combination or single-agent therapy.
Given the role of APEl in DNA repair, inhibition of this enzyme should improve the therapeutic efficacy and clinical outcome of anti-cancer paradigms involving DNA-interactive treatments.