Evaluation of quinazoline analogues as glucocerebrosidase inhibitors with chaperone activity.
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.
NIH Chemical Genomic Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, United States. maruganj@mail.nih.gov
Juan J
JJ
Marugan
Wei
W
Zheng
Omid
O
Motabar
Noel
N
Southall
Ehud
E
Goldin
Wendy
W
Westbroek
Barbara K
BK
Stubblefield
Ellen
E
Sidransky
Ronald A
RA
Aungst
Wendy A
WA
Lea
Anton
A
Simeonov
William
W
Leister
Christopher P
CP
Austin
D002460:Cell Line; D005347:Fibroblasts; D005776:Gaucher Disease / Q000188:drug therapy / Q000201:enzymology; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006923:Hymecromone / Q000031:analogs & derivatives / Q000032:analysis; D007150:Immunohistochemistry; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D018613:Microscopy, Confocal; D018832:Molecular Chaperones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013154:Spleen / Q000201:enzymology / Q000378:metabolism; D013329:Structure-Activity Relationship
D018832:Molecular Chaperones; D011799:Quinazolines; D006923:Hymecromone; D005962:Glucosylceramidase
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