Discovery of Disubstituted Carboranes as Inhibitors of Heat Shock Protein 90-Heat Shock Factor 1 Interaction.

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.