Optimisation of LRRK2 inhibitors and assessment of functional efficacy in cell-based models of neuroinflammation
- Eur J Med Chem. 2015 May 5:95:29-34. doi: 10.1016/j.ejmech.2015.03.003.
- 1. School of Medical Sciences, University of Sydney, NSW 2006, Australia.
- 2. School of Chemistry, University of Sydney, NSW 2006, Australia.
- 3. Australian School of Advanced Medicine, Macquarie University, NSW 2109, Australia.
- 4. School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia; Neuroscience Research Australia, Randwick, NSW 2031, Australia.
- 5. Faculty of Health Sciences, University of Sydney, NSW 2006, Australia.
- 6. School of Chemistry, University of Sydney, NSW 2006, Australia; Faculty of Health Sciences, University of Sydney, NSW 2006, Australia. Electronic address: [email protected].
LRRK2IN1 is a highly potent inhibitor of leucine-rich repeat kinase 2 (LRRK2, IC50 = 7.9 nM), an established target for treatment of Parkinson's disease. Two LRRK2IN1 analogues 1 and 2 were synthesised which retained LRRK2 inhibitory activity (1: IC50 = 72 nM; 2: IC50 = 51 nM), were predicted to have improved bioavailability and were efficacious in cell-based models of neuroinflammation. Analogue 1 inhibited IL-6 secretion from LPS-stimulated primary human microglia with EC50 = 4.26 μM. In order to further optimize the molecular properties of LRRK2IN1, a library of truncated analogues was designed based on docking studies. Despite lacking LRRK2 inhibitory activity, these compounds show anti-neuroinflammatory efficacy at micromolar concentration. The compounds developed were valuable tools in establishing a cell-based assay for assessing anti-neuroinflammatory efficacy of LRRK2 inhibitors. Herein, we present data that IL-1β stimulated U87 glioma cell line is a reliable model for neuroinflammation, as data obtained in this model were consistent with results obtained using primary human microglia and astrocytes.