Ligand-based pharmacophore modelling, structure optimisation, and biological evaluation for the identification of 2-heteroarylthio- N -arylacetamides as novel HSP90 C-terminal inhibitors

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.