2. Academic Validation
  3. Investigation of the site 2 pocket of Grp94 with KUNG65 benzamide derivatives

Investigation of the site 2 pocket of Grp94 with KUNG65 benzamide derivatives

  • Bioorg Med Chem Lett. 2024 Oct 1:111:129893. doi: 10.1016/j.bmcl.2024.129893.
Kyler Pugh 1,  Hao Xu 1,  Brian S J Blagg 2
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, Warren Center for Drug Discovery, The University of Notre Dame, 305 McCourtney Hall, Notre Dame, IN 46556, USA.
  • 2 Department of Chemistry and Biochemistry, Warren Center for Drug Discovery, The University of Notre Dame, 305 McCourtney Hall, Notre Dame, IN 46556, USA. Electronic address: bblagg@nd.edu.
PMID: 39043265 DOI: 10.1016/j.bmcl.2024.129893
Abstract

Glucose-regulated protein 94 (Grp94) is an isoform of the heat shock protein 90 kDa (HSP90) family of molecular chaperones. Inhibiting Grp94 has been implicated for many diseases. Co-crystal structures of two generations of Grp94 inhibitors revealed the importance of investigating the ester group, which is projected into the site 2 pocket unique to Grp94. Therefore, a series of KUNG65 benzamide analogs was designed and synthesized to evaluate their impact on the affinity and selectivity for Grp94. The data demonstrated that substituents with small and saturated ring systems that contain hydrogen bond acceptors exhibited increased affinity for Grp94, whereas larger saturated ring system manifested increased selectivity for Grp94 over Hsp90α.

Keywords

Endoplasmic Reticulum (ER); Grp94; Hsp90; Isoform-selective.

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