Probe compound, ML199, and related inhibitors of Apurinic/apyrimidinic (AP) endonuclease (APE1) are reported herein. APE1 is a key component of the base excision repair (BER) pathway that is responsible for repair of DNA damage caused by many anti-cancer agents such as bleomycin and temozolomide. As a result, inhibition of APE1 has been postulated as a viable strategy for sensitizing tumor cells to chemotherapy. ML199 and its related analogs belong to a drug-like series that was identified and optimized through a focused medicinal chemistry effort to afford compounds which display competitive inhibition of APE1 activity in the low micromolar potency range. On target effect of the ML199 was demonstrated through a concentration depended inhibition of AP site incision activity in whole cell HeLa extracts. Moreover, ML199 potentiated the cytotoxicity of the DNA alkylating agent methylmethane sulfonate (MMS) at non-cytotoxic doses of the probe compound. The probe and its general class of compounds have shown to have good kinetic solubility, Caco-2 permeability, metabolic stability and other favorable physicochemical properties, thus making ML199 an ideal starting point for further pre-clinical development of anti-cancer agents.