ML198

Discovery, SAR, and Biological Evaluation of Non-inhibitory Chaperones of Glucocerebrosidase

PMID:23762943DOI:NBK143537

Gaucher disease is a rare genetic lysosomal storage disease characterized by a loss of function in the glucocerebrosidase (GCase) enzyme, which is responsible for hydrolyzing glucocerebroside (GC) in the lysosome. When cells die, macrophages use GCase to break down GC, a major constituent of cell walls. With deficient functional GCase, GC accumulates within the lysosome, giving rise to the appearance of bloated Gaucher cells; this is a hallmark of the disease. Certain mutated GCase proteins, after production in the endoplasmic reticulum (ER), do not fold properly and are degraded via the proteasome pathway instead of being transported to the lysosome. One therapeutic strategy is to develop small molecule chaperones, which upon binding to GCase ensure proper folding and subsequent transport of the mutant protein to the lysosome, where it can resume activity. The main challenge in the development of molecular chaperones for Gaucher disease is that all of the previously described chaperones are inhibitors of the enzyme. This complicates their clinical development, because it is difficult to generate an appropriate in vivo exposure at which a compound exhibits chaperone activity, but does not inhibit the enzyme’s function. Using high throughput screening, we have identified two chemical series that do not inhibit the enzyme’s action, but can still facilitate its translocation to the lysosome as measured by immunostaining of glucocerebrosidase in patient fibroblasts. These chemical series are exemplified by ML198 and ML266. These compounds serve as starting points to develop a novel approach towards small molecule treatment for patients suffering from Gaucher disease.