ITZ-1, a client-selective Hsp90 inhibitor, efficiently induces heat shock factor 1 activation

Haruhide Kimura; Hiroshi Yukitake; Yasukazu Tajima; Hirobumi Suzuki; Tomoko Chikatsu; Shinji Morimoto; Yasunori Funabashi; Hiroaki Omae; Takashi Ito; Yukio Yoneda; Masayuki Takizawa

doi:10.1016/j.chembiol.2009.12.012

ITZ-1, a client-selective Hsp90 inhibitor, efficiently induces heat shock factor 1 activation

Chem Biol. 2010 Jan 29;17(1):18-27. doi: 10.1016/j.chembiol.2009.12.012.

Authors

Haruhide Kimura¹, Hiroshi Yukitake, Yasukazu Tajima, Hirobumi Suzuki, Tomoko Chikatsu, Shinji Morimoto, Yasunori Funabashi, Hiroaki Omae, Takashi Ito, Yukio Yoneda, Masayuki Takizawa

Affiliation

¹ Pharmaceutical Research Division, Takeda Pharmaceutical, Osaka, Japan.

PMID: 20142037
DOI: 10.1016/j.chembiol.2009.12.012

Abstract

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.

MeSH terms

Adenosine Triphosphate / metabolism
DNA-Binding Proteins / metabolism*
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
Extracellular Signal-Regulated MAP Kinases / metabolism
Gene Expression Regulation / drug effects
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
HSP90 Heat-Shock Proteins / genetics
HSP90 Heat-Shock Proteins / metabolism*
Heat Shock Transcription Factors
Humans
Imidazoles / pharmacology*
Interleukin-1beta / metabolism
Osteoarthritis / drug therapy*
Protective Agents / pharmacology*
Protein Binding
Proto-Oncogene Proteins c-raf / metabolism
Thiazines / pharmacology*
Transcription Factors / metabolism*

Substances

DNA-Binding Proteins
HSF1 protein, human
HSP90 Heat-Shock Proteins
Heat Shock Transcription Factors
Imidazoles
Interleukin-1beta
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
Protective Agents
Thiazines
Transcription Factors
Adenosine Triphosphate
Proto-Oncogene Proteins c-raf
Extracellular Signal-Regulated MAP Kinases