Identification of Inhibitors of the N370S Mutant Form of Glucocerebrosidase as a Potential Therapy for Gaucher Disease

Known glycosidase chaperone molecules belong to the aminosugar class. Because iminosugar inhibitors work by mimicking the transition state of the glycosidic cleavage, they tend to be poorly selective. This has hampered their advance in clinical development. Alternative scaffolds with chaperone activity are quite desirable. In the reports below, we present a new non-aminosugar series of glucocerebrosidase inhibitors having chaperone capacity; ML156 (CID 9893924), is able to inhibit the hydrolytic activity of the N370S mutant form of glucocerebrosidase. We also present ML155 (CID 40225210), a probe that is able to inhibit the hydrolytic activity of the N370S mutant form of glucocerebrosidase, as well as wild type glucocerebrosidase, in tissue homogenate assays. ML155 does not inhibit purified glucocerebrosidase, but the cellular activity of the enzyme is known to be dependent on interactions with other factors, such as Saposin C. Importantly, the probe increased glucocerebrosidase translocation to the lysosome in Gaucher patient-derived fibroblasts homozygous for the N370S mutation, and can be used to study ER-lysosomal trafficking of clinically relevant GC mutants in vitro.

ML155 and ML156

This probe may be a useful lead for the clinical development of a chemical chaperone of glucocerebrosidase. ML156 (CID 9893924) increased glucocerebrosidase translocation to the lysosome in Gaucher patient-derived fibroblasts homozygous for the N370S mutation, and can be used to study ER-lysosomal trafficking of clinically relevant GC mutants in vitro. This probe may be a useful lead for the pre-clinical development of a chemical chaperone of glucocerebrosidase.