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

  title={Novel compounds that reverse the disease phenotype in Type 2 Gaucher disease patient-derived cells.},
  author={W. E. Jun. Childers and Rong Fan and Rogelio Martinez and Dennis J. Colussi and Edward George Melenski and Yu-xiao Liu and John C Gordon and Magid A Abou-Gharbia and Marlene A Jacobson},
  journal={Bioorganic \& medicinal chemistry letters},
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… Expand
2 Citations
The Resurrection of Phenotypic Drug Discovery.
This work highlights some recent phenotypic projects from the industrial past and in the current academic drug discovery environment that have provided encouraging results. Expand
Tamoxifen Derivatives Alter Retromer-Dependent Endosomal Tubulation and Sorting to Block Retrograde Trafficking of Shiga Toxins
It is reported that the activity of tamoxifen against STx1/STx2 is independent of its selective estrogen receptor modulator (SERM) property and instead depends on its weakly basic chemical nature, which allows tamoxIFen to increase endolysosomal pH and alter the recruitment of retromer to endosomes. Expand


Patient-Derived Phenotypic High-Throughput Assay to Identify Small Molecules Restoring Lysosomal Function in Tay–Sachs Disease
A new high-throughput phenotypic assay utilizing infantile Tay–Sachs patient cells based on disrupted lysosomal calcium signaling as a monitor of diseased phenotype will enable the screening of larger chemical compound collections and could lead to identification of new molecular targets previously unknown to impact the disease. Expand
CNS-accessible Inhibitor of Glucosylceramide Synthase for Substrate Reduction Therapy of Neuronopathic Gaucher Disease
Data indicate that an orally available antagonist of GCS that has CNS access is effective at attenuating several of the neuropathologic and behavioral manifestations associated with mouse models of neuronopathic GD, and holds promise as a potential therapeutic approach for patients with type-3 GD. Expand
Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughput screening are chaperone leads for Gaucher disease
Gaucher disease is an autosomal recessive lysosomal storage disorder caused by mutations in the glucocerebrosidase gene. Missense mutations result in reduced enzyme activity that may be due toExpand
ELIGLUSTAT TARTRATE: Glucosylceramide Synthase Inhibitor Treatment of Type 1 Gaucher Disease.
Pre-clinical pharmacological studies demonstrate that the agent has a high therapeutic index, excellent oral bioavailability and limited toxicity, and two randomized phase III trials testing the efficacy and safety of eliglustat tartrate are currently in progress. Expand
Emptying the stores: lysosomal diseases and therapeutic strategies
  • F. Platt
  • Medicine
  • Nature Reviews Drug Discovery
  • 2018
Despite ongoing challenges, various therapeutic strategies for LSDs now exist, with many agents approved, undergoing clinical trials or in preclinical development. Expand
Lysosomal storage diseases
An overview of the LSDs, including how lysosomal dysfunction gives rise to disease and how these disorders are diagnosed and treated, is provided, and an overview of future therapeutic targets for LSDs is provided. Expand
Common and Uncommon Pathogenic Cascades in Lysosomal Storage Diseases*
How pathogenic cascades impact upon LSD pathology are reviewed and how intervention in the pathways may lead to novel therapeutic approaches is suggested. Expand
The Contribution of Mechanistic Understanding to Phenotypic Screening for First-in-Class Medicines
  • D. Swinney
  • Biology, Medicine
  • Journal of biomolecular screening
  • 2013
The format and mechanistic information used to establish the phenotypic assays that led to the first-in-class small-molecule new molecular entities approved by the U.S. Food and Drug Administration between 1999 and 2008 were analyzed and compared with those approved in 2012 and concluded that mechanism takes on different connotations depending on context and perspective. Expand
Prevalence of lysosomal storage disorders.
There was no significant increase in the rate of either clinical diagnoses or prenatal diagnoses of lysosomal storage disorders during the study period, and as a group, they are relatively common and represent an important health problem in Australia. Expand
Lysosomal Ca(2+) homeostasis: role in pathogenesis of lysosomal storage diseases.
A summary of the current knowledge on the role of lysosomal Ca(2+) signaling in the pathogenesis of LSDs is provided, finding that Chediak-Higashi Syndrome cells have been reported to have enhanced lysOSomal Ca (2+) uptake whilst the TRPML1 protein defective in mucolipidosis type IV is believed to function as a Ca( 2+) channel. Expand