Pyrimidinone-peptoid hybrid molecules with distinct effects on molecular chaperone function and cell proliferation

The Hsp70 molecular chaperones are ATPases that play critical roles in the pathogenesis of many human diseases, including breast cancer. Hsp70 ATP hydrolysis is relatively weak but is stimulated by J domain-containing proteins. We identified pyrimidinone-peptoid hybrid molecules that inhibit cell pr...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2008-03, Vol.16 (6), p.3291-3301
Main Authors: Wright, Christine M., Chovatiya, Raj J., Jameson, Nora E., Turner, David M., Zhu, Guangyu, Werner, Stefan, Huryn, Donna M., Pipas, James M., Day, Billy W., Wipf, Peter, Brodsky, Jeffrey L.
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases - metabolism
Antineoplastic agents
Apoptosis
ATP
ATPase
Biginelli
Biological and medical sciences
Breast Neoplasms - drug therapy
Cell Proliferation - drug effects
Chaperone
Dihydropyrimidinone
Female
General aspects
Hsp40
Hsp70
HSP70 Heat-Shock Proteins - antagonists & inhibitors
Humans
J domain
Medical sciences
Molecular Chaperones - drug effects
Peptoids - chemistry
Peptoids - pharmacology
Pharmacology. Drug treatments
Pyrimidinones - chemistry
Pyrimidinones - pharmacology
SK-BR-3
SV40
T antigen
Tetrahydropyrimidinone
Ugi
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Summary:The Hsp70 molecular chaperones are ATPases that play critical roles in the pathogenesis of many human diseases, including breast cancer. Hsp70 ATP hydrolysis is relatively weak but is stimulated by J domain-containing proteins. We identified pyrimidinone-peptoid hybrid molecules that inhibit cell proliferation with greater potency than previously described Hsp70 modulators. In many cases, anti-proliferative activity correlated with inhibition of J domain stimulation of Hsp70.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2007.12.014