Novel nontoxic heat shock protein 90 inhibitors having selective antiproliferative effect.
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.
Tumor Cell Biology Laboratory, Foundation for Cancer Prevention and Effective Treatment, Eötvös Loránd University, Pázmány sétány 1/C, H-1117 Budapest, Hungary. oroszkis@axelero.hu
Antal
A
Orosz
Andrea
A
Szabo
Gabriella
G
Szeman
Tamas
T
Janaky
Csaba
C
Somlai
Botond
B
Penke
Andrea
A
Bodor
Andras
A
Perczel
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002846:Chromatography, Affinity / Q000379:methods; D004305:Dose-Response Relationship, Drug; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D010455:Peptides