Optimisation of LRRK2 inhibitors and assessment of functional efficacy in cell-based models of neuroinflammation Academic Article uri icon

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abstract

  • 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.

authors

  • Steinberg, Gregory
  • Munoz, Lenka
  • Kavanagh, Madeline E
  • Phoa, Athena F
  • Heng, Benjamin
  • Dzamko, Nicolas
  • Chen, Ew-Jun
  • Doddareddy, Munikumar Reddy
  • Guillemin, Gilles J
  • Kassiou, Michael

publication date

  • May 2015

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