A novel PI3K inhibitor XH30 suppresses orthotopic glioblastoma and brain metastasis in mice models

查看全文 作　　者：Ming [1,3]Ji;Dongjie [2]Wang;Songwen [1]Lin;Chunyang [2]Wang;Ling [3]Li;Zhihui [2]Zhang;Jing [1,3]Jin;Deyu [1]Wu;Yi [1]Dong;Heng [1]Xu;Duo [1]Lu;Xiaoguang [1,2]Chen

机构地区：[1]State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;[2]Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;[3]Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China

出　　处：《Acta Pharmaceutica Sinica B》索引2022年第12卷第2期,共13页

基　　金：supported by the CAMS Innovation Fund(2016I2M-3-008,China);The Drug Innovation Major Project(2018ZX09711001-003-011 and 2018ZX09711001-005-017,China);the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences(Grant 2018PT35003,China)。 摘　　要：Glioblastoma is carcinogenesis of glial cells in central nervous system and has the highest incidence among primary brain tumors.Brain metastasis,such as breast cancer and lung cancer,also leads to high mortality.The available medicines are limited due to blood-brain barrier.Abnormal activation of phosphatidylinositol 3-kinases(PI3 K)signaling pathway is prevalent in glioblastoma and metastatic tumors.Here,we characterized a 2-amino-4-methylquinazoline derivative XH30 as a potent PI3 K inhibitor with excellent anti-tumor activity against human glioblastoma.XH30 significantly repressed the proliferation of various brain cancer cells and decreased the phosphorylation of key proteins of PI3 K signaling pathway,induced cell cycle arrest in G1 phase as well.Additionally,XH30 inhibited the migration of glioma cells and blocked the activation of PI3 K pathway by interleukin-17 A(IL-17 A),which increased the migration of U87 MG.Oral administration of XH30 significantly suppressed the tumor growth in both subcutaneous and orthotopic tumor models.XH30 also repressed tumor growth in brain metastasis models of lung cancers.Moreover,XH30 reduced IL-17 A and its receptor IL-17 RA in vivo.These results indicate that XH30 might be a potential therapeutic drug candidate for glioblastoma migration and brain metastasis. 关键词：GLIOBLASTOMA Brain metastasis PI3K-mTOR-AKT signaling pathway PI3K inhibitor IL-17A

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A novel PI3K inhibitor XH30 suppresses orthotopic glioblastoma and brain metastasis in mice models

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