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Novel compounds that reverse the disease phenotype in Type 2 Gaucher disease patient-derived cells.

ABSTRACT: Gaucher disease (GD) results from inherited mutations in the lysosomal enzyme ?-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.

SUBMITTER: Childers W

PROVIDER: S-EPMC7569734 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Novel compounds that reverse the disease phenotype in Type 2 Gaucher disease patient-derived cells.

Childers Wayne W Fan Rong R Martinez Rogelio R Colussi Dennis J DJ Melenski Edward E Liu Yuxiao Y Gordon John J Abou-Gharbia Magid M Jacobson Marlene A MA

Bioorganic & medicinal chemistry letters 20191111 2

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 p ...[more]

PMID: 31757667

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