胶质母细胞瘤（GBM）是一种脑肿瘤，其特点是具有侵袭性和侵袭性。研究发现GBM中STAT3异常激活，抑制STAT3信号传导可有效抑制肿瘤进展。在本研究中，合成了新型嘧啶化合物BY4003和BY4008来靶向JAK3/STAT3信号通路，评估了它们的治疗效果和作用机制，并与托法替尼在U251、A172、LN428和患者来源的胶质母细胞瘤细胞中进行比较。 ADP-Glo​​™ 激酶测定用于评估 BY4003 和 BY4008 对 JAK3（JAK 家族的重要成员）的抑制作用。结果表明，两种化合物均显着抑制 JAK3 酶活性，IC50 值在纳摩尔范围内。通过 MTT 和 H 评估 BY4003、BY4008 和托法替布对 GBM 和患者来源的胶质母细胞瘤细胞的抗增殖作用

Glioblastoma (GBM) is a brain tumor characterized by its aggressive and invasive properties. It is 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 JAK3/STAT3 signaling pathway, and their therapeutic efficacy and mechanisms of action were evaluated and compared with Tofacitinib in U251, A172, LN428 and patient-derived glioblastoma cells. The ADP-Glo™ kinase assay was utilized to assessed the inhibitory effects of BY4003 and BY4008 on JAK3, a crucial member of the JAK family. The results showed that both compounds significantly inhibited JAK3 enzyme activity, with IC50 values in the nanomolar range. The antiproliferative effects of BY4003, BY4008, and Tofacitinib on GBM and patient-derived glioblastoma cells were evaluated by MTT and H&E assays. The impact of BY4003 and BY4008 on GBM cell migration and apoptosis induction was assessed through wound healing, transwell, and TUNEL assays. STAT3-regulated protein expression and relative mRNA levels were analyzed by western blotting, immunocytochemistry, immunofluorescence, and qRT-PCR. It was found that BY4003, BY4008 and Tofacitinib could inhibit U251, A172, LN428 and patient-derived glioblastoma cells growth and proliferation. Results showed decreased expression of STAT3-associated proteins, including p-STAT3, CyclinD1, and Bcl-2, and increased expression of Bax, a pro-apoptotic protein, as well as significant down-regulation of STAT3 and STAT3-related genes. These findings suggested that BY4003 and BY4008 could inhibit GBM growth by suppressing the JAK3/STAT3 signaling pathway, providing valuable insights into the therapeutic development of GBM.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.