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Identification and characterization of small-molecule chaperones of acid alpha glucosidase for potential treatment of Pompe disease

Wednesday, October 10, 2012 — Poster Session II

Noon – 2:00 p.m

Natcher Conference Center, Building 45




  • M.K. Taylor
  • W. Westbroek
  • W. A. Lea
  • A. M. Gustafson
  • A. Velayati
  • W. Zheng
  • N. Southall
  • A. Simeonov
  • E. Goldin
  • E. Sidransky
  • J. J. Marugan
  • J. Xiao


Mutations in the lysosomal enzyme acid alpha-glucosidase (GAA) prevent its translocation from the endoplasmic reticulum to the lysosome and result in its failure to hydrolyze its natural substrate, glycogen. Mutant GAA thus leads to glycogen build-up in the lysosome and ultimately to Pompe disease, a lysosomal storage disorder. The only current therapy for Pompe disease is a costly, inconvenient enzyme replacement therapy, making an alternative treatment desirable. It has been hypothesized that small-molecule chaperones could aid the folding of mutant GAA, thereby increasing its translocation to the lysosome and ameliorating the glycogen build-up characteristic of Pompe disease. From a high-throughput screening campaign we identified a novel series of selective GAA activators, whose potency and efficacy we optimized through extensive medicinal chemistry efforts. Chaperone activity of lead compounds was confirmed by an in vitro binding assay, and these compounds indeed improved GAA translocation to the lysosome in both wild-type and Pompe patient-derived fibroblasts. The compounds displayed favorable pharmacological properties, including aqueous solubility, Caco-2 permeability, and chemical stability in mouse liver microsomes, and they had reasonable pharmacokinetic exposure in mice. By both activating GAA and improving its translocation to the lysosome, these compounds show promise as a potential therapy for Pompe disease.

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