Design and Synthesis of 3-Carbamoylbenzoic Derivatives as Inhibitors of Human Apurinic/Apyrimidinic Endonuclease 1 (APE1)

Apurinic/apyrimidinic (AP) endonuclease (APE1) is a multi-faceted protein with an essential role in the base excision repair (BER) pathway. Its implication in tumor development, progression and resistance has been confirmed in multiple cancers making it a viable target of intense investigation. Here we have designed and synthesized different classes of small molecule inhibitors of APE1’s catalytic endonuclease function containing a 3-carbamoylbenzoic scaffold. Further structural modifications have been made with the aim of increasing activity and cytotoxicity of these inhibitors. Several of our compounds exhibited low micro-molar potencies towards inhibiting APE1’s catalytic endonuclease function in vitro and thus represent novel classes of APE1 inhibitors worthy of further development