Ligand-based Pharmacophore Modelling, Structure Optimisation, and Biological Evaluation for the Identification of 2-heteroarylthio--arylacetamides As Novel HSP90 C-terminal Inhibitors

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2023 Dec 12

PMID 38083866

Authors

Yajun Liu

Chenyao Li

Yajing Li

Shuming Zhang

Ning Zhang

Xiaobo Bian

Shutao Tan

Affiliations

Soon will be listed here.

Abstract

Targeting Heat shock protein 90 (HSP90) C-terminus is an important strategy to develop HSP90 inhibitors without inducing heat shock response. The development of C-terminal inhibitors, however, is hampered by a lack of understanding regarding the interaction between the HSP90 C-terminus and the present inhibitors. We collected seven classical and structurally diverse HSP90 C-terminal inhibitors and constructed a ligand-based pharmacophore model. The subsequent virtual screening and structural optimisation led to the identification of 2-heteroarylthio--arylacetamides as novel HSP90 C-terminal inhibitors. and exhibited strong antitumour activity by inhibiting proliferation and inducing apoptosis in multiple cancer cell lines. These compounds disrupted the interaction between HSP90 C-terminus and peptidylprolyl isomerase D, exerting a stronger inhibitory effect than novobiocin. significantly induced the degradation of HSP90 clients without triggering heat shock response. In an study using 4T1 mice breast cancer models, showed a potent antitumour effect without obvious toxicity.

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