GM1 gangliosidosis and Morquio B are rare lysosomal storage disorders (LSDs) with significant unmet medical needs. These disorders result from mutations in the galactosidase beta 1 (GLB1) gene, leading to impaired β-galactosidase (β-Gal) activity and toxic substrate accumulation. The lack of approved disease-modifying therapies for GM1 gangliosidosis and Morquio B, along with the challenges of achieving effective central nervous system delivery, has driven interest in small-molecule pharmacological chaperones (PCs) to restore β-Gal stability and function. Using Gain Therapeutics’ Magellan™ platform, a novel allosteric binding site on β-Gal was identified, enabling the discovery of a new class of Structurally Targeted Allosteric Regulators (STARs). Medicinal chemistry optimization produced a structurally unique STAR compound series, demonstrating broad β-Gal stabilizing effects. The therapeutic potential of these compounds was evaluated in vitro using a canine fibroblast model of GM1 gangliosidosis, where they were shown to significantly reduce toxic GM1 ganglioside accumulation. Immunocytochemistry-based assays confirmed substrate clearance and provided reliable structure–activity relationships, guiding further compound development. Notably, STARs achieved greater substrate clearance than the competitive PC N-nonyl-deoxygalactonojirimycin (NN-DGJ) under the conditions tested, as demonstrated by immunocytochemistry-based assays. While these findings are encouraging, further in vivo studies are required to validate the therapeutic efficacy of these few STAR compounds, particularly in addressing the neurodegenerative aspects of GM1 gangliosidosis. This study underscores the potential of the Magellan platform in identifying STAR molecules and provides a strong foundation for further optimization and preclinical validation in GLB1-related disorders, particularly GM1 gangliosidosis.
Pérez‐Carmona et al. (Sat,) studied this question.