JZ-4109

JZ-4109 is a modulator of β-glucocerebrosidase (GCase) with an IC50 of 8 nM for the wild-type recombinant GCase. It binds to the allosteric site at the dimer interface of GCase, stabilizing both the wild-type and GCaseN370S mutant forms, and induces dimerization of GCase. Additionally, JZ-4109 increases the abundance of the GCase protein and is applicable in research related to Parkinson's disease.

JZ-4109 (Compound 3) effectively inhibits wild-type recombinant GCase through a linear mixed-type inhibition with an IC50 of 8 nM when used at concentrations ranging from 0.76 nM to 1.56 μM over 30 minutes. At concentrations of 0.25-100 μM and when heated from 20 °C to 95 °C at a rate of 0.1 °C/s, JZ-4109 stabilizes wild-type recombinant GCase against thermal denaturation. In healthy control human fibroblasts, a concentration of 0.2-2 μM of JZ-4109 over 3 days significantly increases GCase protein abundance and enzyme activity without altering GBA mRNA levels. Additionally, at 2 μM for 3 days, it promotes the maturation and transport of GCase to post-endoplasmic reticulum compartments in fibroblasts without increasing endoplasmic reticulum retention. Furthermore, JZ-4109 enhances GCase abundance and enzyme activity within the lysosomal compartment of HEK cells at 2 μM over 3 days. In fibroblasts from type 1 Gaucher disease donors with the homozygous GBA N370S mutation, JZ-4109 at 0.2-2 μM over 3 days significantly elevates the abundance and activity of post-endoplasmic reticulum mature GCase protein. Finally, when co-incubated with 16.5 μM GCase at concentrations ranging from 4.12-33.0 μM, JZ-4109 induces dose-dependent dimerization of wild-type GCase in solution.