Discovery and Basic Research

Keynote: Isoform-Selective Inhibition of Hsp90 Affords New Opportunities to Treat Cancer, Diseases of the CNS, and Glaucoma

Keynote Speaker(s)

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  Brian Blagg, PhD

  Director, The Warren Center for Drug Discovery
  University of Notre Dame

Moderator(s)

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  Patrick Ronaldson, PhD, FAAPS (he/him/his)

  Professor
  University of Arizona
  Tucson, Arizona

The 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 denatured proteins. The cytostolic chaperones, Hsp90a and Hsp90b, contribute to tumorogenesis and represent attractive targets for the treatment of cancer. Grp94 is the ER-localized paralog and is responsible for the trafficking of proteins, such as myocillin, and consequently represents a promising target for the treatment of primary open angle glaucoma. In contrast to the inhibition of Hsp90, the molecular chaperones can be overexpressed to exhibit neuroprotective activity in animal models of neuropathy. 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, methods used to develop isoform-selective inhibitors will be disclosed as well as some preclinical studies that have been pursued for the translation of these inhibitors for the treatment of cancer, glaucoma, and neurodegeneration.