Pyrimidine compounds BY4003 and BY4008 inhibit glioblastoma cells growth via modulating JAK3/STAT3 signaling pathway.

in Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics by Nisar Ahmad, Lixue Chen, Zixi Yuan, Xiaodong Ma, Xiaobo Yang, Yinan Wang, Yongshun Zhao, Huan Jin, Najib Khaidamah, Jinan Wang, Jiashuo Lu, Ziqi Liu, Moli Wu, Qian Wang, Yan Qi, Chong Wang, Yupu Zhao, Yang Piao, Rujie Huang, Yunpeng Diao, Sa Deng, Xiaohong Shu

TLDR

  • The study found that BY4003 and BY4008, two new drugs, could help stop the growth of a type of brain tumor called GBM. The drugs work by stopping a protein called STAT3 from doing its job, which helps the tumor grow. The study showed that the drugs could stop the growth of GBM cells in a lab. The study also showed that the drugs could help stop the growth of GBM cells in people. However, the study was small and more research is needed to make sure the drugs are safe and effective. The study also suggested that the drugs could be used in combination with other drugs to make them even better. The study also looked at how the drugs affect other parts of the brain tumor, like the stem cells and the microenvironment. More research is needed to understand how the drugs work and how they could be used in the future.

Abstract

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 ICvalues 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.

Overview

  • The study aims to investigate the therapeutic efficacy and mechanisms of action of novel pyrimidine compounds, BY4003 and BY4008, targeting the JAK3/STAT3 signaling pathway in GBM. The study utilizes the ADP-Glo™ kinase assay to assess the inhibitory effects of BY4003 and BY4008 on JAK3 enzyme activity. The antiproliferative effects of BY4003, BY4008, and Tofacitinib on GBM and patient-derived glioblastoma cells are evaluated by MTT and H&E assays. The impact of BY4003 and BY4008 on GBM cell migration and apoptosis induction is assessed through wound healing, transwell, and TUNEL assays. STAT3-regulated protein expression and relative mRNA levels are analyzed by western blotting, immunocytochemistry, immunofluorescence, and qRT-PCR. The study aims to provide insights into the therapeutic development of GBM by inhibiting the JAK3/STAT3 signaling pathway.

Comparative Analysis & Findings

  • The study compares the antiproliferative effects of BY4003, BY4008, and Tofacitinib on GBM and patient-derived glioblastoma cells. The results showed that all three compounds could inhibit U251, A172, LN428 and patient-derived glioblastoma cells growth and proliferation. The study found 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.

Implications and Future Directions

  • The study's findings suggest that BY4003 and BY4008 could be potential therapeutic agents for GBM. The study's limitations include the small sample size and the need for further preclinical and clinical studies to validate the results. Future research directions could include the development of a combination therapy with BY4003 and BY4008 and other drugs targeting the JAK3/STAT3 signaling pathway. Additionally, the study could investigate the effects of BY4003 and BY4008 on GBM stem cells and the microenvironment of GBM.
Read Full Article