DNL201 (GNE0877) is a first-in-class, CNS-penetrant, selective, ATP-competitive, small-molecule LRRK2 kinase inhibitor with IC50 of 3 nM.
DNL201 inhibited LRRK2 kinase activity by reduced phosphorylation of both LRRK2 at serine-935 (pS935) and Rab10 at threonine-73 (pT73), a direct substrate of LRRK2.
DNL201 demonstrated improved lysosomal function in cellular models of disease, including primary mouse astrocytes and fibroblasts from patients with Gaucher disease.
DNL201 shows the potential to correct lysosomal dysfunction in patients with Parkinson's disease (PD) in clinical investigations.
