Published as: Gavenonis, Jason, Nicholas E. Jonas, and Joshua A. Kritzer. Potential C-terminal-domain Inhibitors of Heat Shock Protein 90 Derived from a C-terminal Peptide Helix. Bioorganic and Medicinal Chemistry 22, no.15 (2014): 3989-3993. https://www.sciencedirect.com/science/article/pii/S0968089614004490#! This author post-print is made available on Dickinson Scholar with the permission of the publisher. For more information on the published version, visit ScienceDirect's Website.

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.