1264534-10-2Relevant articles and documents
Evaluation of quinazoline analogues as glucocerebrosidase inhibitors with chaperone activity
Marugan, Juan J.,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 P.
, p. 1033 - 1058 (2011/04/25)
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.
