Work

Optimization of triazole-based small molecule disruptors of the Aha1/Hsp90 complex that manifest potent activities

Year: 2026

Type: article

Abstract: Recent structure-activity relationship (SAR) studies identified multiple Hsp90/Aha1 small molecule disruptors that manifest moderately improved potencies and physiochemical properties. Among these molecules, a 1,5-bisubstituted-1,2,3-triazole containing molecule (Triazole A), demonstrated the importance of a cis -amide bond. Consequently, this work aimed to optimize Triazole A via a nitrogen scan and Topliss tree approach. The potency was determined against cell lysates and co-Immunoprecipitation (co-IP) experiments. The most efficacious molecules were evaluated for physiochemical properties that include aqueous solubility, human liver microsome half-life, and MDCK-MDR1 permeability. New molecules emerged from this study that manifest nanomolar potency and improved activity in cell-based co-IP experiments. These new molecules represent a significant improvement over prior Hsp90/Aha1 disruptors and provide chemical tools to investigate the significance of Hsp90/Aha1 complexes. • Optimized molecules manifest greater than 100-fold improved potencies. • Reduced doses led to significant disruption of Hsp90/Aha1 in cellulo. • 37b exhibited improved solubility, h LM half-life and efflux ratio.

Source: European Journal of Medicinal Chemistry

DOI: 10.1016/j.ejmech.2026.118612

Authors: Kevin C. Catalfano, Margaret H. Rakonick, 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: hybrid

Estimated APC paid: $4,650