Additional file 1 of LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology progression

Additional file 1. Table S1: Characterization of PHF preparations from AD brains. Figure S1: Long-term MLi-2 impacts lung, but not the gross kidney morphology. Figure S2: Quantitative pathology workflow. Figure S3: Quantitative pathology analysis from all mice. Figure S4: Sex differences in tau pathology in wild-type mice. Figure S5: Representative staining from 3 MPI mice. Figure S6: Wild-type compared to LRRK2G2019S mice at 3 MPI. Figure S7: Tau pathology compared by treatment group at 3 MPI. Figure S8: Representative staining from 6 MPI mice. Figure S9: Examination of linear diffusion fits by hemisphere. Figure S10: Microglia quantification in caudal cortex of 6 MPI mice

Discovery of a 3‑(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity

Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson’s disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (<b>1</b>): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2