MGAP-9

MGAP-9 is a novel hybrid small molecule designed to overcome temozolomide (TMZ) resistance in glioblastoma (GBM) by simultaneously inhibiting two key DNA repair mechanisms: O6-methylguanine-DNA methyltransferase (MGMT) and the base excision repair (BER) enzyme apurinic/apyrimidinic endonuclease 1 (APE1). Developed by researchers at Texas Tech University Health Sciences Center, MGAP-9 is chemically synthesized by linking the 3-hydroxybenzyl nitrate moiety of nitroaspirin (an MGMT inhibitor) with 7-nitroindole-2-carboxylic acid (an APE1 inhibitor) through an ester bond. In preclinical studies, MGAP-9 demonstrated the ability to sensitize GBM cell lines to methylating agents like TMZ and dacarbazine, reduced tumor growth in orthotopic mouse models, and exhibited antiangiogenic activity without significant systemic toxicity.