Synthesis and Evaluation of Small Molecule Disruptors of the Aha1/Hsp90 Complex for the Reduction of Tau Aggregation

KU-177 was recently shown to disrupt interactions between HSP90 and Aha1 in vitro. Subsequent studies in recombinant thioflavin T (ThT) assays demonstrated that KU-177 ablates Aha1-driven enhancement of Hsp90-dependent tau aggregation, which was confirmed by TEM. Using KU-177 as a lead compound, derivatives of KU-177 were synthesized and evaluated for their ability to disrupt Aha1/HSP90 interactions and inhibit P301L tau aggregation. Preliminary structure-activity relationships were revealed, which led to the identification of a new lead compound that contains a cis-like amide bond. The new lead compounds retain the ability to disrupt Aha1/HSP90 interactions in SH-SY5Y and SK-BR-3 cells without direct inhibition of HSP90, providing a new scaffold for subsequent drug discovery efforts.