标题：Discovery of Small-Molecule Inhibitors of the HSP90-Calcineurin-NFAT Pathway against Glioblastoma
作者：Liu, Zhenzhen; Li, Hongli; He, Lian; Xiang, Yu; Tian, Chengsen; Li, Can; Tang, Peng; Jing, Ji; Tian, Yanpin; Du, Lupei; Huang, Yun 更多 作者机构：[Liu, Zhenzhen; Li, Hongli; He, Lian; Li, Can; Tang, Peng; Jing, Ji; Huang, Yun; Zhou, Yubin] Texas A&M Univ, Inst Biosci & Technol, Coll Med, Houston 更多
通讯作者：Zhou, YB;Li, MY;Han, L;Li, MY;Zhou, YB
通讯作者地址：[Zhou, YB]Texas A&M Univ, Inst Biosci & Technol, Coll Med, Houston, TX 77030 USA;[Li, MY]Shandong Univ, Sch Pharm, Dept Med Chem, Key Lab Chem Biol MO 更多
来源：CELL CHEMICAL BIOLOGY
关键词：calcineurin; cancer therapy; cell signaling; click chemistry; drug screening; gene expression; glioblastoma; HSP90 inhibitor; NFAT; proteomics
摘要：Glioblastoma (GBM) is among the most common and malignant types of primary brain tumors in adults, with a dismal prognosis. Although alkylating agents such as temozolomide are widely applied as the first-line treatment for GBM, they often cause chemoresistance and remain ineffective with recurrent GBM. Alternative therapeutics against GBM are urgently needed in the clinic. We report herein the discovery of a class of inhibitors (YZ129 and its derivatives) of the calcineurin-NFAT pathway that exhibited potent anti-tumor activity against GBM. YZ129-induced GBM cell-cycle arrest at the G2/M phase promoted apoptosis and inhibited tumor cell proliferation and migration. At the molecular level, YZ129 directly engaged HSP90 to antagonize its chaperoning effect on calcineurin to abrogate NFAT nuclear translocation, and also suppressed other proto-oncogenic pathways including hypoxia, glycolysis, and the PI3K/AKT/mTOR signaling axis. Our data highlight the potential for targeting the cancer-promoting HSP90 chaperone network to treat GBM.