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Childers W , Fan R , Martinez R , Colussi DJ , Melenski E , Liu Y , Gordon J , Abou-Gharbia M , Jacobson MA
Novel compounds that reverse the disease phenotype in Type 2 Gaucher disease patient-derived cells
Bioorg Med Chem Lett. 2020 Jan 15;30(2) :126806
PMID: 31757667    PMCID: PMC7569734   
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Gaucher disease (GD) results from inherited mutations in the lysosomal enzyme β-glucocerobrosidase (GCase). Currently available treatment options for Type 1 GD are not efficacious for treating neuronopathic Type 2 and 3 GD due to their inability to cross the blood-brain barrier. In an effort to identify small molecules which could be optimized for CNS penetration we identified tamoxifen from a high throughput phenotypic screen on Type 2 GD patient-derived fibroblasts which reversed the disease phenotype. Structure activity studies around this scaffold led to novel molecules that displayed improved potency, efficacy and reduced estrogenic/antiestrogenic activity compared to the original hits. Here we present the design, synthesis and structure activity relationships that led to the lead molecule Compound 31.
1464-3405 Childers, Wayne Fan, Rong Martinez, Rogelio Colussi, Dennis J Melenski, Edward Liu, Yuxiao Gordon, John Abou-Gharbia, Magid Jacobson, Marlene A S10 OD018195/OD/NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Bioorg Med Chem Lett. 2020 Jan 15;30(2):126806. doi: 10.1016/j.bmcl.2019.126806. Epub 2019 Nov 11.