College of Pharmacy, Dalian Medical University, Dalian 116044, China; College of Basic Medical Science, Dalian Medical University, Dalian 116044, China; Institute of Integrative Medicine, Dalian Medical University, Dalian 116044, China.
College of Pharmacy, Dalian Medical University, Dalian 116044, China.
Neurotherapeutics. 2024 Sep;21(5):e00431. doi: 10.1016/j.neurot.2024.e00431. Epub 2024 Aug 16.
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 IC 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.
胶质母细胞瘤（GBM）是一种具有侵袭性和侵略性的脑肿瘤。研究发现，STAT3 在 GBM 中异常激活，抑制 STAT3 信号通路可以有效抑制肿瘤进展。在本研究中，合成了新型嘧啶类化合物 BY4003 和 BY4008，以靶向 JAK3/STAT3 信号通路，并评估了它们与 Tofacitinib 在 U251、A172、LN428 和患者来源的胶质母细胞瘤细胞中的治疗效果和作用机制。利用 ADP-Glo™激酶测定法评估了 BY4003 和 BY4008 对 JAK3（JAK 家族的关键成员）的抑制作用。结果表明，这两种化合物均能显著抑制 JAK3 酶的活性，IC 值均在纳摩尔范围内。通过 MTT 和 H&E 测定法评估了 BY4003、BY4008 和 Tofacitinib 对 GBM 和患者来源的胶质母细胞瘤细胞的增殖抑制作用。通过划痕愈合、Transwell 和 TUNEL 测定法评估了 BY4003 和 BY4008 对 GBM 细胞迁移和凋亡诱导的影响。通过 Western blot、免疫细胞化学、免疫荧光和 qRT-PCR 分析了 STAT3 调节蛋白的表达和相对 mRNA 水平。结果表明，BY4003、BY4008 和 Tofacitinib 能够抑制 U251、A172、LN428 和患者来源的胶质母细胞瘤细胞的生长和增殖。结果显示，p-STAT3、CyclinD1 和 Bcl-2 等 STAT3 相关蛋白表达降低，促凋亡蛋白 Bax 表达增加，STAT3 和 STAT3 相关基因表达显著下调。这些发现表明，BY4003 和 BY4008 可以通过抑制 JAK3/STAT3 信号通路抑制 GBM 的生长，为 GBM 的治疗开发提供了有价值的见解。
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