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Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Structure-Activity Relationship Study of Tertiary Alcohol Hsp90α-Selective Inhibitors with Novel Binding Mode
Sanket J Mishra1, Tyelor S Reynolds1, Taylor Merfeld1
1Department of Chemistry and Biochemistry, The University of Notre Dame, 305 McCourtney Hall, Notre Dame, Indiana 46556, United States.
Abstract:
The heat shock protein 90 (Hsp90) family of molecular chaperones mediates the folding and activation of client proteins associated with all 10 hallmarks of cancer. Herein, the design, synthesis, and biological validation of Hsp90α-selective inhibitors that contain a tertiary alcohol are reported. Forty-one analogues were synthesized to modulate hydrogen-bonding interactions and to probe for steric and hydrophobic interactions within the Hsp90α binding site. Cocrystal structures of lead compound 23d (IC50 = 0.25 μM, 15-fold selective vs Hsp90β) and a 5-fluoroisoindoline derivative (KUNA-111) revealed a novel binding mode that induced conformational changes within Hsp90α's N-terminal domain. The lead Hsp90α-selective inhibitors did not manifest significant antiproliferative activity, but they did result in selective and dose-dependent degradation of Hsp90α clients in the cellular environment. Additional studies will be sought to determine the effects of the novel conformational change induced by 23d.
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