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

Bradley M Keegan; Kevin C Catalfano; Monimoy Banerjee; Brian S J Blagg

doi:10.1021/acsmedchemlett.2c00064

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

ACS Med Chem Lett. 2022 Apr 15;13(5):827-832. doi: 10.1021/acsmedchemlett.2c00064. eCollection 2022 May 12.

Authors

Bradley M Keegan¹, Kevin C Catalfano¹, Monimoy Banerjee¹, Brian S J Blagg¹

Affiliation

¹ Warren Center for Drug Discovery, Department of Chemistry and Biochemistry, University of Notre Dame, 310 McCourtney Hall, Notre Dame, Indiana 46556, United States.

Abstract

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.

Abstract

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