Novel nontoxic heat shock protein 90 inhibitors having selective antiproliferative effect

Antal Orosz, Andrea Szabo, Gabriella Szeman, T. Janáky, C. Somlai, B. Penke, A. Bodor, A. Perczel

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Almost all heat shock protein 90 inhibitors reported so far, which are natural product derivatives, have problems mainly with toxic side effects, and with bioavailability and solubility. In our earlier studies, we compared the steric conformational structures of substance P[6-11] with our substance P antagonists in silico, and used the diverse biological effects of these compounds as tools in our modeling and design studies for discovering antiproliferative drugs. Here, we present a new synthesized short peptide-derivative compound family that inhibits only the function of the tumor cell's heat shock protein 90 and selectively kills in vitro more cancer cells than normal cells. During the lead generation, we observed that the difference between the most effective inhibitors was only one residue or group that caused diverse effects in vitro on the studied cell lines. According to our in vivo experiments on nude mice bearing lung cancer xenografts, the inhibitors restrained tumor growth, but not caused overt toxicity. We undertook NMR spectroscopy studies to analyze the 3D molecular structural differences of our inhibitors that control their binding to the target molecule. In conclusion, we demonstrated the efficacy of new selective and small molecule anticancerogen heat shock protein 90 inhibitors with peptide nature, without in vivo toxicity on nude mouse xenograft model. Our results also shed light on the mechanism of anticancerogen action of some substance P antagonists and their derivatives.

Original languageEnglish
Pages (from-to)1352-1362
Number of pages11
JournalInternational Journal of Biochemistry and Cell Biology
Volume38
Issue number8
DOIs
Publication statusPublished - 2006

Fingerprint

HSP90 Heat-Shock Proteins
Cells
Substance P
Derivatives
Heterografts
Nude Mice
Toxicity
Tumors
Bearings (structural)
Neoplasms
Peptides
Molecules
Poisons
Biological Products
Computer Simulation
Solubility
Biological Availability
Nuclear magnetic resonance spectroscopy
Lung Neoplasms
Magnetic Resonance Spectroscopy

Keywords

  • 3D molecular structure
  • Anticancerogen
  • Hsp90 inhibitor
  • Peptide-derivative
  • Selective activity

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Cite this

Novel nontoxic heat shock protein 90 inhibitors having selective antiproliferative effect. / Orosz, Antal; Szabo, Andrea; Szeman, Gabriella; Janáky, T.; Somlai, C.; Penke, B.; Bodor, A.; Perczel, A.

In: International Journal of Biochemistry and Cell Biology, Vol. 38, No. 8, 2006, p. 1352-1362.

Research output: Contribution to journalArticle

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