Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold

J Med Chem. 2016 Apr 14;59(7):3471-88. doi: 10.1021/acs.jmedchem.6b00085. Epub 2016 Apr 4.

Abstract

Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum resident of the heat shock protein 90 kDa (Hsp90) family of molecular chaperones. Grp94 associates with many proteins involved in cell adhesion and signaling, including integrins, Toll-like receptors, immunoglobulins, and mutant myocilin. Grp94 has been implicated as a target for several therapeutic areas including glaucoma, cancer metastasis, and multiple myeloma. While 85% identical to other Hsp90 isoforms, the N-terminal ATP-binding site of Grp94 possesses a unique hydrophobic pocket that was used to design isoform-selective inhibitors. Incorporation of a cis-amide bioisostere into the radamide scaffold led to development of the original Grp94-selective inhibitor, BnIm. Structure-activity relationship studies have now been performed on the aryl side chain of BnIm, which resulted in improved analogues that exhibit better potency and selectivity for Grp94. These analogues also manifest superior antimigratory activity in a metastasis model as well as enhanced mutant myocilin degradation in a glaucoma model compared to BnIm.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetanilides / chemistry*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzoates / chemistry*
  • Binding Sites
  • Blotting, Western
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Cytoskeletal Proteins / metabolism*
  • Eye Proteins / metabolism*
  • Female
  • Glaucoma / drug therapy
  • Glycoproteins / metabolism*
  • Humans
  • Hydroxybenzoates / chemistry
  • Hydroxybenzoates / pharmacology*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Membrane Glycoproteins / metabolism
  • Protein Binding
  • Proteolysis
  • Structure-Activity Relationship
  • Wound Healing / drug effects

Substances

  • Acetanilides
  • Antineoplastic Agents
  • Benzoates
  • Cytoskeletal Proteins
  • Eye Proteins
  • Glycoproteins
  • Hydroxybenzoates
  • Imidazoles
  • Membrane Glycoproteins
  • endoplasmin
  • methyl 2-(2-(1-benzyl-1H-imidazol-2-yl)ethyl)-3-chloro-4,6-dihydroxybenzoate
  • radamide
  • trabecular meshwork-induced glucocorticoid response protein