Inhibitors of the Hsp90 C-terminus
Hsp90 is a promising therapeutic target for the treatment of cancer and neurodegenerative diseases. While current research focuses on drugging the N-terminal ATP-binding pocket, small molecules that disrupt the Hsp90 C-terminus manifest distinctive properties and may provide additional advantages over N-terminal inhibitors. Structural modifications to novobiocin, the first Hsp90 C-terminal inhibitor identified, have led to a set of analogues that either induce a strong heat shock response or manifest potent anti-proliferative activities. The development of these novobiocin-based analogues and their biological evaluation is summarized in this chapter. Additional small molecules that bind the Hsp90 C-terminus are also discussed.