Development of Phenyl Cyclohexylcarboxamides as a Novel Class of Hsp90 C-terminal Inhibitors

Abstract

Inhibition of the heat shock protein 90 (Hsp90) C-terminus represents a promising therapeutic strategy for the treatment of cancer. Novobiocin, a coumarin antibiotic, was the first Hsp90 C-terminal inhibitor identified, however, it manifested poor anti-proliferative activity (SKBr3, IC₅₀ ≈700 μm). Subsequent structure-activity relationship (SAR) studies on novobiocin led to development of several analogues that exhibited improved anti-proliferative activity against several cancer cell lines. Recent studies demonstrate that the biphenyl core could be used in lieu of the coumarin ring system, which resulted in more efficacious analogues. In continuation of previous efforts, the work described herein has identified the phenyl cyclohexyl core as a novel scaffold for Hsp90 C-terminal inhibition. Structure-activity relationship (SAR) studies on this scaffold led to the development of compounds that manifest mid-nanomolar activity against SKBr3 and MCF-7 breast cancer cell lines through Hsp90 inhibition.

Keywords: breast cancer; heat shock protein 90; hsp90 c-terminal inhibitors; phenyl cyclohexylcarboxamides; structure-activity relationship.