Discovery, SAR, and Biological Evaluation of a Non-Inhibitory Chaperone for Acid Alpha Glucosidase

Glycogen storage disease II, or Pompe disease, is a rare and often fatal autosomal recessive lysosomal storage disorder (LSD) caused by the dysfunction of the lysosomal enzyme acid alpha-glucosidase (GAA). Accumulation of GAA’s substrate, glycogen, causes enlargement of cellular lysosomes, adversely affecting many cells, especially heart and skeletal muscle tissues. The only FDA approved treatment for Pompe disease is enzyme replacement therapy, called Myozyme, which has significant limitations. Importantly, of the over 100 different mutations known to cause Pompe disease, many retain enzymatic activity in vitro, although the structural changes induced by mutants affect trafficking of the enzyme to the lysosome. Small molecule chaperones can be used to correct this trafficking defect. These compounds bind to the protein in the endoplasmic reticulum, accelerating the folding process and increasing their translocation to the lysosome, thereby reducing substrate accumulation. Several iminosugar inhibitors of GAA, such duvoglustat, are known to chaperone the translocation of mutant GAA proteins. However, their impact on substrate reduction may be limited by their continued inhibition of the target enzyme, as well as limited selectivity towards GAA. We have previously reported an inhibitor (ML201) and through further work, we have now also identified the first non-inhibitory small molecule chaperone of acid alpha glucosidase, ML247. Here, we demonstrate that ML247 enhances mutant enzyme translocation using Pompe patient-derived fibroblasts. ML247 displays reasonable pharmacokinetics and might serve as a pivotal first step in efforts to develop a non-inhibitory molecular chaperone for the treatment of Pompe disease.