title: Optimisation of LRRK2 inhibitors and assessment of functional efficacy in cell-based models of neuroinflammation.
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: School of Medical Sciences, University of Sydney, NSW 2006, Australia.
authors: Lenka
authors: L
authors: Munoz
authors: School of Chemistry, University of Sydney, NSW 2006, Australia.
authors: Madeline E
authors: ME
authors: Kavanagh
authors: School of Medical Sciences, University of Sydney, NSW 2006, Australia.
authors: Athena F
authors: AF
authors: Phoa
authors: Australian School of Advanced Medicine, Macquarie University, NSW 2109, Australia.
authors: Benjamin
authors: B
authors: Heng
authors: School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia; Neuroscience Research Australia, Randwick, NSW 2031, Australia.
authors: Nicolas
authors: N
authors: Dzamko
authors: School of Medical Sciences, University of Sydney, NSW 2006, Australia.
authors: Ew-Jun
authors: EJ
authors: Chen
authors: Faculty of Health Sciences, University of Sydney, NSW 2006, Australia.
authors: Munikumar Reddy
authors: MR
authors: Doddareddy
authors: Australian School of Advanced Medicine, Macquarie University, NSW 2109, Australia.
authors: Gilles J
authors: GJ
authors: Guillemin
authors: School of Chemistry, University of Sydney, NSW 2006, Australia; Faculty of Health Sciences, University of Sydney, NSW 2006, Australia. Electronic address: michael.kassiou@sydney.edu.au.
authors: Michael
authors: M
authors: Kassiou
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D001570:Benzodiazepinones; D053583:Interleukin-1beta; D015850:Interleukin-6; C582847:LRRK2-IN1; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
keywords: LRRK2 inhibitors; Neuroinflammation; Structure–activity relationships