Identification of a New Scaffold for Hsp90 C-Terminal Inhibition

Inhibition of Hsp90 C-terminal function is an advantageous therapeutic
paradigm for the treatment of cancer. Currently, the majority of Hsp90
C-terminal inhibitors are derived from novobiocin, a natural product
traditionally used as an antibiotic. Assisted by molecular docking
studies, a scaffold containing a biphenyl moiety in lieu of the coumarin
ring system found in novobiocin was identified for development of new
Hsp90 C-terminal inhibitors. Initial structure-activity studies led to
derivatives that manifest good antiproliferative activity against two
breast cancer cell lines through Hsp90 inhibition. This platform serves
as a scaffold upon which new Hsp90 C-terminal inhibitors can be readily
assembled for further investigation.