Evaluation of quinazoline analogues as glucocerebrosidase inhibitors with chaperone activity.

Medicinal Chemistry

Abstract

Gaucher disease is a lysosomal storage disorder (LSD) caused by deficiency in the enzyme glucocerebrosidase (GC). Small molecule chaperones of protein folding and translocation have been proposed as a promising therapeutic approach to this LSD. Most small molecule chaperones described in the literature contain an iminosugar scaffold. Here we present the discovery and evaluation of a new series of GC inhibitors with a quinazoline core. We demonstrate that this series can improve the translocation of GC to the lysosome in patient-derived cells. To optimize this chemical series, systematic synthetic modifications were performed and the SAR was evaluated and compared using three different readouts of compound activity: enzymatic inhibition, enzyme thermostabilization, and lysosomal translocation of GC.

Authors

Marugan, Juan; Zheng, Wei; Motabar, Omid; Southall, Noel; Goldin, Ehud; Westbroek, Wendy; Stubblefield, Barbara K; Sidransky, Ellen; Aungst, Ronald A; Lea, Wendy A; Simeonov, Anton; Leister, William; Austin, Christopher;

Keywords

  • Cell Line
  • Fibroblasts
  • Gaucher Disease/ drug therapy
  • Gaucher Disease/ enzymology
  • Glucosylceramidase/ antagonists & inhibitors
  • Glucosylceramidase/ chemistry
  • Glucosylceramidase/ metabolism
  • Humans
  • Hymecromone/ analogs & derivatives
  • Hymecromone/ analysis
  • Immunohistochemistry
  • Lysosomes/ drug effects
  • Lysosomes/ enzymology
  • Lysosomes/ metabolism
  • Magnetic Resonance Spectroscopy
  • Microscopy, Confocal
  • Molecular Chaperones/ chemical synthesis
  • Molecular Chaperones/ chemistry
  • Molecular Chaperones/ pharmacology
  • Quinazolines/ chemical synthesis
  • Quinazolines/ chemistry
  • Quinazolines/ pharmacology
  • Spectrometry, Mass, Electrospray Ionization
  • Spleen/ enzymology
  • Spleen/ metabolism
  • Structure-Activity Relationship

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