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Title
Japanese:Discovery of Disubstituted Carboranes as Inhibitors of Heat Shock Protein 90窶滴eat Shock Factor 1 Interaction 
English:Discovery of Disubstituted Carboranes as Inhibitors of Heat Shock Protein 90窶滴eat Shock Factor 1 Interaction 
Author
Japanese: Yujie Shao, Kazuki Miura, Yasunobu Asawa, Taiki Morita, Guangzhe Li, Hiroyuki Nakamura.  
English: Yujie Shao, Kazuki Miura, Yasunobu Asawa, Taiki Morita, Guangzhe Li, Hiroyuki Nakamura.  
Language English 
Journal/Book name
Japanese:ACS Medicinal Chemistry Letters 
English:ACS Medicinal Chemistry Letters 
Volume, Number, Page Vol. 15    No. 5    pp. 619-625
Published date Apr. 8, 2024 
Publisher
Japanese:American Chemical Society 
English:American Chemical Society 
Conference name
Japanese: 
English: 
Conference site
Japanese: 
English: 
Official URL https://doi.org/10.1021/acsmedchemlett.4c00022
 
DOI https://doi.org/10.1021/acsmedchemlett.4c00022
Abstract Efficient synthesis of disubstituted para- and ortho-carboranes (2 and 3, respectively) was achieved. Among the compounds synthesized, 3e showed potent suppression of hypoxia-inducible factor 1 (HIF-1) transcriptional activity under hypoxia by a cell-based reporter gene assay. Detailed mechanism-of-action studies revealed that 3e reduced the stability of heat shock protein (HSP) 90 client proteins such as CDK4, AKT, and cyclin D1 by inhibiting HSP90 chaperone activity but did not induce a heat shock response (HSR), which may cause drug resistance. Furthermore, 3e inhibited the interaction between HSP90 and heat shock factor 1 (HSF1), resulting in reducing HSF1 protein stability and thereby suppressing the transcription of heat shock proteins.

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