Potential C-terminal-domain inhibitors of heat shock protein 90 derived from a C-terminal peptide helix.

Hsp90 is a molecular chaperone implicated in many diseases including cancer and neurodegenerative disease. Most inhibitors target the ATPase site in Hsp90's N-terminal domain, with relatively few inhibitors of other domains reported to date. Here, we show that peptides derived from a short helix at the C-terminus of Hsp90 show micromolar activity as Hsp90 inhibitors in vitro. These inhibitors do not block the N-terminal domain's ATP-binding site, and thus are likely to bind at the C-terminal domain. Substitutions and helix stapling were applied to demonstrate structure-activity relationships and improve activity. These helical peptides will help guide the design of a new class of inhibitors of Hsp90's C-terminal domain.