Development of Hsp90/Aha1 Small Molecule Disruptors for the Treatment of Tauopathies

The Blagg research lab is an interdisciplinary group that designs, synthesizes and evaluates novel small molecules that modulate the activity of Hsp90, while avoiding deleterious on-target toxicities. Among these are small molecules that disrupt Hsp90/Aha1 complexes. This approach allows us to modulate the proteostatic network under the control of Hsp90 in various disease states ranging from cancer to neurodegenerative disease. My thesis work has focused on the design, synthesis, evaluation and optimization of Hsp90/Aha1 small molecule disruptors. These molecules represent an interesting avenue to treat diseases arising from chaperone/co-chaperone interactions by modulating the Hsp90 ATPase rate directly tied to the folding function, while retaining Hsp90 protein folding activity.

Through the course of my thesis work, we have developed new scaffolds to optimize Hsp90/Aha1 disruptors and new molecules that exhibit >100-fold improvements in efficacy compared to leads with improved physiochemical properties, which represent promising candidates for subsequent in vivo studies. Tauopathies are characterized by chronic neuroinflammation that drives the accumulation of toxic aggregates and induces neurodegeneration. These improved Hsp90/Aha1 disruptors have demonstrated efficacy in BV2 microglia by manifesting an anti-oxidative phenotype, which is favorable in neurodegenerative and neuroinflammatory conditions. Collectively, this work presents new molecules for in vivo evaluation and a novel application of Hsp90/Aha1 small molecule disruptors.