Hsp90 (heat shock protein 90) is a ubiquitous chaperone protein that has been extensively studied as a target for new cancer therapies. The majority of Hsp90 inhibitors are small molecules that target the ATP-binding pocket in the protein's N-terminal domain. To discover complementary modes of Hsp90 inhibition, we used Hsp90 crystal structures to design peptide-based inhibitors that could mimic surfaces involved in Hsp90's protein-protein interactions.  From these, a peptide inhibiting Hsp90 at the C-terminus was found to have 20-fold greater potency than the known small-molecule C-terminal inhibitor novobiocin, and the manner in which it inhibits the Hsp90 chaperone cycle was further elucidated through cell culture and pull-down assays.

Exploring alternate modes of Hsp90 inhibition with peptides

246th National Meeting (2013)

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