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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Calcineurin / metabolism
  • Calcium / metabolism
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Drug Evaluation, Preclinical
  • Drug Resistance, Neoplasm / drug effects
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Glioblastoma / drug therapy
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Glycolysis / drug effects
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Mice
  • Mice, Nude
  • NFATC Transcription Factors / metabolism
  • Signal Transduction / drug effects*
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / therapeutic use
  • Transplantation, Heterologous


  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins
  • NFATC Transcription Factors
  • Small Molecule Libraries
  • Calcineurin
  • Calcium