Antitumor activity of SNX-2112, a synthetic heat shock protein-90 inhibitor, in MET-amplified tumor cells with or without resistance to selective MET Inhibition

Clin Cancer Res. 2011 Jan 1;17(1):122-33. doi: 10.1158/1078-0432.CCR-10-0253.


Purpose: Heat shock protein-90 (HSP-90), a molecular chaperone required by numerous oncogenic kinases [e.g., HER-2, epidermal growth factor receptor (EGFR), Raf-1, v-Src, and AKT] for conformational stability, has attracted wide interest as a novel target for cancer therapy. HSP-90 inhibition induces degradation of HSP-90 client proteins, leading to a combinatorial inhibition of multiple oncogenic signaling pathways with consecutive growth arrest and apoptosis. MET, a tyrosine kinase that is constitutively active in tumor cells with MET oncogene amplification, has recently been identified as another HSP-90 client.

Experimental design: The aim of our study was to assess the efficacy of SNX-2112, a synthetic HSP-90 inhibitor, in 3 different MET-amplified tumor cell lines (GTL-16, MKN-45, and EBC-1) as well as PR-GTL-16 cells, a GTL-16 subline selected for resistance to the highly selective MET kinase inhibitor PHA-665752.

Results: In all cell lines, SNX-2112 led to degradation of MET, HER-2, EGFR, and AKT, as well as abrogation of Ras/Raf/MEK/MAPK and PI3K/AKT signaling, followed by complete cell cycle arrest. SNX-5542, an orally bioavailable prodrug of SNX-2112, displayed significant antitumor efficacy in vivo in nude mice bearing MET-amplified tumor xenografts. Importantly, HSP-90 inhibition maintained its antitumor efficacy in PR-GTL-16 cells both in vitro and in vivo, suggesting that HSP-90 inhibition could be a particularly valuable strategy in MET-amplified tumors that have acquired resistance to MET kinase inhibition.

Conclusions: Our study provides evidence for the efficacy of HSP-90 inhibition in MET-amplified cancer cells, particularly when MET kinase inhibitor resistance has emerged.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Humans
  • Indoles / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / metabolism
  • Structure-Activity Relationship
  • Sulfones / pharmacology


  • 5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one
  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins
  • Heterocyclic Compounds, 4 or More Rings
  • Indoles
  • Protein Kinase Inhibitors
  • SNX 2112
  • Sulfones
  • Proto-Oncogene Proteins c-met