Abstract
The heat shock protein 90 (Hsp90) molecular chaperone is composed of four family members that play key roles in the folding of nascent polypeptides as well as the rematuration of misfolded proteins. The cytosolic chaperones, Hsp90a and Hsp90b, contribute to tumorigenesis and represent attractive targets for the treatment of cancer. Grp94 is the endoplasmic reticulumlocalized paralog that is responsible for the trafficking of proteins, such as myocilin, and consequently represents an ideal target for the treatment of primary open-angle glaucoma. In contrast to the inhibition of Hsp90, molecular chaperones can be overexpressed to exhibit neuroprotective activity, which is currently undergoing phase II clinical evaluation. While the Hsp90 isoforms play key roles in various diseases, the N-terminal ATP-binding site is >85% identical, making the development of selective inhibitors challenging. In this presentation, the methods used to develop isoform-selective inhibitors will be disclosed, along with some of the preclinical studies that are currently underway.
Citation: Proceedings of the 8th International Conference on PharmScience Research & Development (Pharma R&D-2026). USG Proc J 2(Suppl 12): S1-S16.
