Biotinylated Hsp90β-selective inhibitors

Abstract

Heat shock protein 90 (Hsp90) has emerged as an attractive target for the development of therapeutics against cancer due to its crucial role in the folding and stabilization of client proteins associated with oncogenesis. Hsp90 pan inhibitors entered clinical trials for the treatment of cancer and showed detrimental adverse effects. Hsp90α isoform inhibition has been attributed to on-target toxicities such as cardio- and ocular-toxicity. To determine whether off-target toxicities caused by the interaction of Hsp90β inhibitors with other cellular proteins, biotinylated Hsp90β-selective inhibitors with various tether lengths were synthesized and validated in vitro to be used in affinity purification experiments to identify proteins that interact with Hsp90β-selective inhibitors. These studies will lead to the development of Hsp90β-selective inhibitors with reduced toxicities.