Discovery of potent heat shock protein 90 (Hsp90) inhibitors: structure-based virtual screening, molecular dynamics simulation, and biological evaluation

Abstract

Heat shock protein 90 (Hsp90) is considered an attractive therapeutic target for cancer treatment due to its high expression in many cancers. In this study, four potent Hsp90 inhibitors (HPs 1–4) were identified using structure-based virtual screening. Among them, HP-4 exhibited the most potent inhibitory effects (IC₅₀ = 17.64 ± 1.45 nM) against the Hsp90 protein, which was about 7.7 times stronger than that of MPC-3100 (a positive inhibitor targeting Hsp90). In vitro cytotoxicity assay suggested that HP-4 could effectively inhibit the proliferation of a series of tumour cells, including HCT-116, HeLa, A549, A2780, DU145, HepG2 and A498. Furthermore, in vivo assay displayed that HP-4 had significant anti-tumour effects on HCT-116 cell-derived xenograft models. These data demonstrate that HP-4 could be a potential lead compound for the further investigation of anti-tumour drugs.

Keywords:

• Hsp90
• inhibitor
• virtual screening
• colon cancer
• biological evaluation

Ethical statement

All experimental protocols were reviewed and approved by the Animal Ethics Committee of China Pharmaceutical University.

Author contributions

YX, YZ and SZ performed experiments and acquired data. YX, YZ and SZ collected experimental samples. MMN and YZ performed statistical analysis. JL, YZ, ZX and LY analysed data and wrote the paper. All authors had edited and approved the final manuscript.

Disclosure statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

Additional information

Funding

This study is supported by Jiangsu Research Hospital Association for Precision Medication [JY202229] and Fengcheng Talent Plan Youth Science and Technology Talent Recruitment Project of Taizhou [202210].