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A compound that inhibits the HOP-Hsp90 complex formation and has unique killing effects in breast cancer cell lines

Genaro Pimienta1, Kristina M Herbert, Lynne Regan

  • 1Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States.

Molecular Pharmaceutics
|September 3, 2011
PubMed

Insights

A novel Hsp90 inhibitor, C9, effectively kills breast cancer cells by disrupting chaperone interactions without inducing Hsp70 upregulation. C9 enhances the efficacy of existing Hsp90 inhibitors and counteracts their prosurvival effects.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Drug Discovery

Background:

  • Heat shock protein 90 (Hsp90) is crucial for folding client proteins, especially oncogenic ones in cancer cells.
  • Current Hsp90 inhibitors targeting the ATP-binding site, like 17-AAG and PU-H71, show promise but induce Hsp70, which promotes cancer cell survival.
  • There is a need for novel Hsp90 inhibitors with improved therapeutic profiles.

Purpose of the Study:

  • To characterize a new Hsp90 inhibitor, C9 (1,6-dimethyl-3-propylpyrimido[5,4-e][1,2,4]triazine-5,7-dione).
  • To evaluate C9's mechanism of action and its efficacy against breast cancer cells.
  • To assess C9's effect on Hsp70 expression and its potential to overcome resistance to existing Hsp90 inhibitors.

Main Methods:

  • In vitro assays using purified proteins to determine C9's interaction with Hsp90 and its cochaperone HOP.
  • In vitro studies on various breast cancer cell lines, including MDA-MB-231, to assess C9's cytotoxicity.
  • Analysis of Hsp70 transcriptional upregulation in cells treated with C9 alone or in combination with other Hsp90 inhibitors (17-AAG, NVP-AUY922).

Main Results:

  • C9 inhibits Hsp90's interaction with the cochaperone HOP, disrupting the Hsp90 folding pathway.
  • C9 demonstrates significant efficacy in killing various breast cancer cell lines, including highly metastatic MDA-MB-231.
  • Unlike existing inhibitors, C9 does not induce Hsp70 transcriptional upregulation and counteracts the Hsp70 overexpression caused by 17-AAG or NVP-AUY922.
  • Combination therapy with C9 and existing Hsp90 inhibitors reduced C9's lethal IC50, indicating enhanced efficacy.

Conclusions:

  • C9 represents a novel class of Hsp90 inhibitors that target Hsp90-cochaperone interactions.
  • C9 exhibits potent anticancer activity against breast cancer cells and offers a distinct advantage by not inducing Hsp70-mediated prosurvival effects.
  • C9 has the potential to be used in combination therapies to enhance the efficacy of existing Hsp90 inhibitors and overcome resistance mechanisms.

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