TY - JOUR
T1 - Conversion of Quinazoline Modulators from Inhibitors to Activators of β-Glucocerebrosidase
AU - Zheng, Jianbin
AU - Jeon, Sohee
AU - Jiang, Weilan
AU - Burbulla, Lena F.
AU - Ysselstein, Daniel
AU - Oevel, Kristine
AU - Krainc, Dimitri
AU - Silverman, Richard B.
N1 - Funding Information:
This work was supported by NIH R01NS076054, R01NS096240, WildKat and Buckeye Research LLC (to D.K.) and The Michael J. Fox Foundation for Parkinson’s Research (to J.Z.). This work made use of the IMSERC at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF NNCI-1542205); the State of Illinois and International Institute for Nanotechnology (IIN). We would like to thank H. Goudarzi and S. Shafaie in IMSERC at Northwestern University for their assistance with HRMS experiments. We thank the Northwestern Stem Cell Core Facility for the generation of iPSC lines from the GBA1 mutation carrier.
PY - 2019/2/14
Y1 - 2019/2/14
N2 - Gaucher's disease is a lysosomal disease caused by mutations in the β-glucocerebrosidase gene (GBA1 and GCase) that have been also linked to increased risk of Parkinson's disease (PD) and Diffuse Lewy body dementia. Prior studies have suggested that mutant GCase protein undergoes misfolding and degradation, and therefore, stabilization of the mutant protein represents an important therapeutic strategy in synucleinopathies. In this work, we present a structure-activity relationship (SAR) study of quinazoline compounds that serve as inhibitors of GCase. Unexpectedly, we found that N-methylation of these inhibitors transformed them into GCase activators. A systematic SAR study further revealed that replacement of the key oxygen atom in the linker of the quinazoline derivative also contributed to the activity switch. PD patient-derived fibroblasts and dopaminergic midbrain neurons were treated with a selected compound (9q) that partially stabilized GCase and improved its activity. These results highlight a novel strategy for therapeutic development of noninhibitory GCase modulators in PD and related synucleinopathies.
AB - Gaucher's disease is a lysosomal disease caused by mutations in the β-glucocerebrosidase gene (GBA1 and GCase) that have been also linked to increased risk of Parkinson's disease (PD) and Diffuse Lewy body dementia. Prior studies have suggested that mutant GCase protein undergoes misfolding and degradation, and therefore, stabilization of the mutant protein represents an important therapeutic strategy in synucleinopathies. In this work, we present a structure-activity relationship (SAR) study of quinazoline compounds that serve as inhibitors of GCase. Unexpectedly, we found that N-methylation of these inhibitors transformed them into GCase activators. A systematic SAR study further revealed that replacement of the key oxygen atom in the linker of the quinazoline derivative also contributed to the activity switch. PD patient-derived fibroblasts and dopaminergic midbrain neurons were treated with a selected compound (9q) that partially stabilized GCase and improved its activity. These results highlight a novel strategy for therapeutic development of noninhibitory GCase modulators in PD and related synucleinopathies.
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U2 - 10.1021/acs.jmedchem.8b01294
DO - 10.1021/acs.jmedchem.8b01294
M3 - Article
C2 - 30645117
AN - SCOPUS:85061632342
VL - 62
SP - 1218
EP - 1230
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 3
ER -