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Cell Chem Biol. 2019 Mar 21;26(3):352-365.e7. doi: 10.1016/j.chembiol.2018.11.009. Epub 2019 Jan 10.

Discovery of Small-Molecule Inhibitors of the HSP90-Calcineurin-NFAT Pathway against Glioblastoma.

Author information

1
Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China; Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Materials Science, Shandong Normal University, Jinan, Shandong 250014, China.
2
Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA; Department of Histology and Embryology, Army Medical University, Chongqing 400038, China.
3
Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA.
4
Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA.
5
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China; School of Chemistry and Chemical Engineering, Qilu Normal University, Jinan, Shandong 250200, China.
6
Department of Histology and Embryology, Army Medical University, Chongqing 400038, China.
7
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China.
8
Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA. Electronic address: leng.han@uth.tmc.edu.
9
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China; State Key Laboratory of Microbial Technology, Shandong University, Jinan, Shandong 250100, China. Electronic address: mli@sdu.edu.cn.
10
Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA; Department of Medical Physiology, College of Medicine, Texas A&M University, Temple, TX 76504, USA. Electronic address: yzhou@ibt.tamhsc.edu.

Abstract

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.

KEYWORDS:

HSP90 inhibitor; NFAT; calcineurin; cancer therapy; cell signaling; click chemistry; drug screening; gene expression; glioblastoma; proteomics

PMID:
30639261
PMCID:
PMC6430684
[Available on 2020-03-21]
DOI:
10.1016/j.chembiol.2018.11.009

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