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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, N.I.H., Intramural
MeSH terms
-
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
Substances
-
Molecular Chaperones
-
Quinazolines
-
Hymecromone
-
Glucosylceramidase