Pyrimidine Compounds By4003 and By4008 Inhibit Glioblastoma Cells Growth Via Modulating Stat3 Signaling Pathway

Glioblastoma (GBM) is a highly malignant brain tumor characterized by its aggressive and invasive properties. It was found that STAT3 is abnormally activated in GBM, and inhibiting STAT3 signaling can effectively suppress tumor progression. In this study, novel pyrimidine compounds BY4003 and BY4008 were synthesized to target the JAK/STAT3 signaling, and their therapeutic efficacy and related mechanisms in GBM U251, A172 and LN428 cells were investigated. The inhibitory effect of BY4003/BY4008 on JAK3, a key member of the JAK family, was evaluated using the ADP-Glo™ Kinase Assay. Results showed that BY4003/BY4008 significantly inhibited the enzymatic activity of JAK3 with IC50 values in the nanomolar range. The anti-proliferative effects of BY4003/BY4008 on GBM cells were assessed through MTT, H&E, wound healing and TUNEL assays. Analysis of STAT3-regulated protein expression and relative mRNA levels was conducted through western blotting, immunocytochemistry and RT-qPCR. Results indicated reduced expression of STAT3-associated proteins (p-STAT3, CyclinD-1 and Bcl-2) and increased expression of Bax, a pro-apoptotic protein, as well as significant down-regulation of STAT3 and STAT3-related genes. The findings suggested that BY4003/BY4008 could inhibit GBM growth by suppressing the JAK3/STAT3 signaling pathway, which would provide valuable insights for the therapeutic development of GBM.