The development of new methods to treat cancer is greatly needed. The Hsp90 protein folding machinery has been the target of significant interest for the development of anti-cancer agents. However, Hsp90 is responsible for the folding of ~300 protein folding substrates, which may lead to undesired on-target toxicity and may be responsible for many of the Hsp90-targeted drugs that have failed in clinical trials. Through a structure-based approach, an isoform-selective inhibitor of Hsp90 has been identified and shown to exhibit good selectivity and affinity against particular cancers. Consequently, the goal of this application is to optimize this new inhibitory scaffold for great affinity/efficacy, to evaluate the role of a specific Hsp90 isoform in cancer, and to validate this isoform as a target for the treatment of bladder cancer.
There are four Hsp90 isoforms that together, are responsible for the conformational maturation/activation of >300 client proteins. Due to the role played by these client proteins in signaling cascades, Hsp90 has evolved into a highly sought after target for the development of new anti-cancer agents. Unfortunately, detriments associated with pan-inhibition of all four Hsp90 isoforms have arisen, supporting the development of isoform-selective inhibitors. This application aims to develop Hsp90b-selective inhibitors for the potential treatment of bladder cancer, the fifth most common cancer in the US.