Synthesis and evaluation of pyrimidine derivatives for Glioblastoma Multiforme inhibition

Glioblastoma Multiforme (GBM) is a fatal brain tumor with limited treatment options. Here, we report KJ-25, a novel pyrimidine-based dual PI3K/mTOR inhibitor designed to overcome the limitations of current therapies like GDC-0084 (Paxalisib). Through structure-oriented optimization, the efficacy of KJ-25 on human GBM cell lines and primary tumor cells of Hras-shTp53-driven mouse model is higher than that of GDC-0084. In terms of mechanism, KJ-25 exhibits superior inhibition of the PI3K/mTOR signaling pathway and almost completely inhibits phosphorylation of AKT (Ser473) and its downstream effectors at low nanomolar concentrations. In an orthotopic transplantation GBM model, compared with GDC-0084, KJ-25 significantly suppressed tumor growth. These results suggest that KJ-25 is a promising candidate drug for the treatment of GBM, providing a strategy for improving the prognosis of this refractory malignant tumor.