LAUSR

High grade gliomas (HGG) carry poor prognosis with median survival rates under 15 months post diagnosis. Due to dysregulation of kinase signaling pathways within these tumors, targeted kinase inhibition has been considered as a promising clinical strategy. However in HGG, many single-agent inhibitors of EGFR or PI3K have shown limited response due to activation of compensatory signaling. Single-molecule multikinase inhibitors may decrease resistance, present a single pharmacokinetic dosage profile, and reduce risks of multi-agent toxicities, supporting this strategy over dual drug combination approaches. To test this concept, a panel of inhibitors exploiting known binding modes of structurally-related ATP binding site inhibitors of EGFR/PI3K were synthesized and characterized. Of these, MTX-241 was least likely to act as a substrate for drug efflux proteins such as P-glycoprotein. Treatment of MTX-241 in a panel of eight human adult and pediatric HGG lines showed strong cytotoxic potency measured by growth inhibitory activity, with IC50s in the < 10 µM range. Tumor selectivity of MTX-241 was observed, with normal human astrocytes (NHA) nearly insensitive to MTX-241 even at >100 µM. MTX-241 was significantly more potent than clinically relevant inhibitors targeting EGFR/RTKs (gefitinib, lapatinib, dasatinib, imatinib) or PI3K (alpelisib, idelalisib). Synthesis and evaluation of a new series of compounds based on MTX-241 structure, but optimized for improved stability is ongoing. Our data suggests that a dual inhibitor of EGFR and PI3K, represents a viable therapeutic strategy in adult and pediatric HGG. Future studies will focus on evaluation of in vivo efficacy in tumor bearing mouse models.