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Attempts to Achieve Targeted Covalent Inhibition of Hsp90β.

Terin D'Amico1, Tyelor S Reynolds1, Michael A Serwetnyk1

  • 1Department of Chemistry and Biochemistry, Warren Center for Drug Discovery, The University of Notre Dame, Notre Dame, Indiana, USA.

Chemical Biology & Drug Design
|April 12, 2026
PubMed
Summary

Targeted covalent inhibitors targeting lysine residues show promise for Hsp90β inhibition. While selectivity remains a challenge, new compounds demonstrate favorable binding kinetics to Hsp90β.

Keywords:
FluorosulfonylHsp90Hsp90βMichael acceptorsacrylamidesisoform‐selective inhibitionlysinetargeted covalent inhibition

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Area of Science:

  • Biochemistry
  • Chemical Biology
  • Drug Discovery

Background:

  • Targeted covalent inhibition utilizes warheads for specific amino acid modification.
  • Lysine is an emerging target for covalent modification due to its abundance and importance.
  • Current inhibitors struggle to differentiate between highly similar Hsp90α and Hsp90β isoforms.

Purpose of the Study:

  • To develop Hsp90β-selective covalent inhibitors targeting lysine residues.
  • To investigate the efficacy of novel electrophilic warheads for Hsp90β inhibition.
  • To analyze the binding kinetics and selectivity of newly designed compounds.

Main Methods:

  • Structure-based drug design to identify Hsp90β-selective inhibitors.
  • Incorporation of electrophilic warheads onto inhibitor scaffolds.
  • Kinetic analysis of inhibitor binding to the Hsp90 N-terminal ATP-binding pocket.
  • Assessment of covalent modification at Lys58.

Main Results:

  • Novel compounds exhibited favorable binding to Hsp90β.
  • Confirmation of covalent modification at Lys58 was inconclusive.
  • Some compounds showed highest affinity for Hsp90β after 2-hour incubation.
  • Inhibitor binding kinetics to the Hsp90 N-terminal ATP-binding pocket were determined.

Conclusions:

  • Developing Hsp90β-selective covalent inhibitors targeting lysine is feasible.
  • Further optimization is needed to confirm covalent modification and improve selectivity.
  • Understanding binding kinetics provides insights for future drug design targeting Hsp90 isoforms.