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 ... read morenot 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.read less
Gavenonis, J.; Jonas, N. E.; Kritzer, J. A. Potential C-Terminal-Domain Inhibitors of Heat Shock Protein 90 Derived from a C-Terminal Peptide Helix. Bioorganic & Medicinal Chemistry 2014, 22 (15), 3989-3993 DOI: 10.1016/j.bmc.2014.06.006.