Small Molecule Modulation of the Hsp90 Proteostasis Network for Neuropathic Protection

The Blagg research lab is an interdisciplinary medicinal chemistry and chemical biology team focused on the rational design of new molecules and advancing putative therapeutic agents that target the 90 kDa Heat Shock Protein (Hsp90) and its proteostasis network for the treatment of cancer, Alzheimer's disease, and glaucoma. Within this context, my thesis work has focused on the design, synthesis, and evaluation of small molecule disruptors of Aha1/Hsp90 interactions for the reduction of tau aggregation; the development of a novel in vitrosplit Renilla luciferaseassay for assessment of Aha1/Hsp90 disruptors; and the biological evaluation of small molecule inhibitors of tumor necrosis factor receptor-associated protein 1 (TRAP1), the mitochondrial Hsp90 paralog.

Supporting evidence and information from these studies helped to guide the development of both Hsp90/Aha1 disruptors and TRAP1-targeting molecules. The work and methodologies described herein have provided a foundation for the evaluation of small molecule modulators of these specific Hsp90 networks, with the goal of identifying compounds that exhibit increased efficacy and potency toward their biological targets. Such molecules can be used to reveal the cellular processes and pathways that mediate the neuroprotective effect manifested by these molecules in models of AD, PD, and other neuropathies.