Work

Optimization of Hsp90/Aha1 Small-Molecule Disruptors Via the Evaluation of Amide Bioisosteres

Year: 2025

Type: article

Abstract: Recent structure–activity relationships (SAR) were established around KU-177, the parent scaffold for an Hsp90/Aha1 small-molecule disruptor, which suggested that the central amide linker adopted a cis -amide conformation for the inhibitory activity. In this Letter, a series of analogues was synthesized to contain various amide bioisosteres, which were evaluated for their ability to disrupt Hsp90/Aha1 interactions. The inhibitory activity was determined with recombinant protein as well as co-immunoprecipitation experiments with cell lysates. The most efficacious scaffolds were assessed for solubility, metabolic stability, and permeability, where the most efficacious molecule was the sulfonamide-containing compound 44 . New molecules emerged from this study and will be optimized in subsequent SAR campaigns.

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.5c00592

Authors: Kevin C. Catalfano, Bradley M. Keegan, Brian S. J. Blagg

Institution: University of Notre Dame

Language: English

Topic: Heat shock proteins research

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green