Abstract 1013 Optimization of Small Molecule Disruptors of the Hsp90/Aha1 Complex for the Treatment of Tauopathies

Recently, we demonstrated KU-177 as an effective Hsp90/ Aha1 disruptor in vitro.These studies indicated that KU-177 was effective at blocking Hsp90/Aha1 driven tau aggregation in vitro by both ThT aggregation assays and TEM images.Using KU-177 as a lead compound, we synthesized and evaluated derivatives for their ability to disrupt Hsp90/Aha1 interactions via co-immunoprecipitation and block Hsp90/Aha1 driven P301L tau aggregation in ThT assays.Preliminary structure-activity relationships were revealed, which led to identification of a new lead compound, ND-AHA-46, which contains a cis-like geometry.ND-AHA-46 retains activity as a Hsp90/Aha1 disruptor in both SH-SY5Y and SK-BR-3 cells without direct inhibition of Hsp90, and thus represents a new scaffold for therapeutic optimization.This new lead was pursued through a series of analogs probing the central amide for necessary geometry and ideal heteroatom substituents.The results of this study yielded compounds with improved efficacy and physiochemical properties such as half-life and aqueous solubility.Further SAR studies are underway to optimize the best new scaffolds as potential drug candidates.