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

Yujie Shao; Kazuki Miura; Yasunobu Asawa; Taiki Morita; Guangzhe Li; Hiroyuki Nakamura

doi:10.1021/acsmedchemlett.4c00022

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

ACS Med Chem Lett. 2024 Apr 8;15(5):619-625. doi: 10.1021/acsmedchemlett.4c00022. eCollection 2024 May 9.

Authors

Yujie Shao¹, Kazuki Miura^{1

2}, Yasunobu Asawa¹, Taiki Morita^{1

2}, Guangzhe Li³, Hiroyuki Nakamura^{1

2}

Affiliations

¹ School of Life Science and Technology, Tokyo Institute of Technology, 4259, Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan.
² Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, 4259, Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan.
³ State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China.

PMID: 38746882
PMCID: PMC11089554 (available on 2025-05-09)
DOI: 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.