ITZ-1, a client-selective Hsp90 inhibitor, efficiently induces heat shock factor 1 activation.
ITZ-1 is a chondroprotective agent that inhibits interleukin-1beta-induced matrix metalloproteinase-13 (MMP-13) production and suppresses nitric oxide-induced chondrocyte death. Here we describe its mechanisms of action. Heat shock protein 90 (Hsp90) was identified as a specific ITZ-1-binding protein. Almost all known Hsp90 inhibitors have been reported to bind to the Hsp90 N-terminal ATP-binding site and to simultaneously induce degradation and activation of its multiple client proteins. However, within the Hsp90 client proteins, ITZ-1 strongly induces heat shock factor-1 (HSF1) activation and causes mild Raf-1 degradation, but scarcely induces degradation of a broad range of Hsp90 client proteins by binding to the Hsp90 C terminus. These results may explain ITZ-1's inhibition of MMP-13 production, its cytoprotective effect, and its lower cytotoxicity. These results suggest that ITZ-1 is a client-selective Hsp90 inhibitor.
Pharmaceutical Research Division, Takeda Pharmaceutical, Osaka, Japan.
Haruhide
H
Kimura
Hiroshi
H
Yukitake
Yasukazu
Y
Tajima
Hirobumi
H
Suzuki
Tomoko
T
Chikatsu
Shinji
S
Morimoto
Yasunori
Y
Funabashi
Hiroaki
H
Omae
Takashi
T
Ito
Yukio
Y
Yoneda
Masayuki
M
Takizawa
D000255:Adenosine Triphosphate / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D010003:Osteoarthritis / Q000188:drug therapy*; D020011:Protective Agents / Q000494:pharmacology*; D011485:Protein Binding; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D013843:Thiazines / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000255:Adenosine Triphosphate; D004268:DNA-Binding Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D007093:Imidazoles; D053583:Interleukin-1beta; D020011:Protective Agents; D019908:Proto-Oncogene Proteins c-raf; D013843:Thiazines; D014157:Transcription Factors; C000619706:HSF1 protein, human; C542558:N-(5,6-dimethyl-3-oxo-8-((4,4,5,5,5-pentafluoropentyl)thio)-2,3-dihydro-1H-imidazo(5,1-c)(1,4)thiazin-1-ylidene)-4-methylbenzenesulfonamide; D005466:Fluorocarbons; D000096926:Benzenesulfonamides