Geldanamycin derivative inhibition of HGF/SF-mediated Met tyrosine kinase receptor-dependent urokinase-plasminogen activation.
Ansamycins, including geldanamycin and the derivative 17-allylamino-17-demethoxygeldanamycin, and radicicol are known for their ability to tightly bind to the ATP-binding site of the amino-terminal domain region of heat shock protein 90. We have found that geldanamycin and some of its derivatives can inhibit hepatocyte growth factor/scatter factor-mediated Met tyrosine kinase receptor-dependent urokinase-plasminogen activation at femtomolar levels. Assessment is made of structural requirements for such an activity and evidence is given that distinguishes the target of such an activity from that of heat shock protein 90.
Department of Physiology, Michigan State University, East Lansing, MI 48864, USA.
Yuehai
Y
Shen
Qian
Q
Xie
Monica
M
Norberg
Edward
E
Sausville
George
G
Vande Woude
David
D
Wenkert
D016227:Benzoquinones; D045744:Cell Line, Tumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic; D007783:Lactones / Q000378:metabolism / Q000494:pharmacology; D018942:Macrolides; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011809:Quinones / Q000378:metabolism / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D017828:Rifabutin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D007783:Lactones; D018942:Macrolides; C524898:PLAUR protein, human; D047428:Protein Kinase Inhibitors; D011809:Quinones; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D017828:Rifabutin; C112765:tanespimycin; D017228:Hepatocyte Growth Factor; C035359:monorden; C001277:geldanamycin