Inhibition of Hsp90: a new strategy for inhibiting protein kinases.
The 90-kDa heat shock protein (Hsp90) is a ubiquitous, evolutionarily highly conserved, molecular chaperone in the eukaryotic cytosol. Hsp90, together with a number of other chaperones, promotes the conformational maturation of a large variety of protein kinases. Inhibition of Hsp90 function results in the collapse of the metastable conformation of most of these kinases and leads to their proteolytic elimination by the proteasome. Numerous natural and synthetic Hsp90 inhibitors have been developed in recent years. Some of these inhibitors are also involved in sensitizing tumor cells to pro-apoptotic insults, hence serve as anti-cancer drugs. Here we review these novel protein kinase inhibitors and their emerging role in various cellular processes, apart from their inhibition of Hsp90 protein function. We focus not only on Hsp90-tumor progression, but also on cytoarchitecture, as the higher levels of cellular organization need constant remodeling, where the role of Hsp90 requires investigation. Our last major aspect deals with protein oxidation, since several Hsp90 inhibitors exert pro-oxidant effects.
Sreedhar
Amere Subbarao
AS
Department of Medical Chemistry, Semmelweis University Medical School, P.O. Box 260, H-1444 Budapest 8, Hungary.
Soti
Csaba
C
Csermely
Péter
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D018384:Oxidative Stress; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000737:chemistry; D015398:Signal Transduction
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases