Design, synthesis and biological evaluation of biphenylamide derivatives as Hsp90 C-terminal inhibitors

• A small library of biphenylamide derivatives was designed and analogs synthesized.
• Compounds were evaluated for anti-proliferative activity against cancer cell lines.
• Hsp90 inhibition was confirmed by Western blot analysis.
• Several analogs showed low nanomolar inhibitory activity.

Modulation of Hsp90 C-terminal function represents a promising therapeutic approach for the treatment of cancer and neurodegenerative diseases. Current drug discovery efforts toward Hsp90 C-terminal inhibition focus on novobiocin, an antibiotic that was transformed into an Hsp90 inhibitor. Based on structural information obtained during the development of novobiocin derivatives and molecular docking studies, scaffolds containing a biphenyl moiety in lieu of the coumarin ring present in novobiocin were identified as new Hsp90 C-terminal inhibitors. Structure–activity relationship studies produced new derivatives that inhibit the proliferation of breast cancer cell lines at nanomolar concentrations, which corresponded directly with Hsp90 inhibition.

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