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Discovery of enhancers of the secretion of leukemia inhibitory factor for the treatment of multiple sclerosis

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Vela, Laura and Caballero, Iván and Fang, Leiping and Liu, Qin and Ramón Olayo, Fernando Antonio and Díez, Emilio and Frailes, Maite de los (2015) Discovery of enhancers of the secretion of leukemia inhibitory factor for the treatment of multiple sclerosis. Journal of Biomolecular Screening, 21 (5). pp. 437-445. ISSN 1087-0571

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Abstract

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease that involves activation of T cells, microglia, and astrocytes. There is a clear unmet medical need for MS, as current therapies reduce the relapse rate, but are unable to prevent the neurological deterioration. Leukemia inhibitory factor (LIF) is a proinflammatory cytokine that can also positively modulate the immune response, by inducing the inhibition of myelin-reactive TH17 differentiation, and by promoting oligodendrocyte-mediated myelination. The aim of this project was to find central nervous system (CNS)– permeable and orally available small molecules that upregulate production of endogenous LIF. We describe here the development of a phenotypic assay and screening of 1.7 million compounds to identify LIF enhancers using U87 MG cells. Five chemically tractable series of compounds and a few singletons were selected for further progression. Some of them were also active in a different LIF-expressing cell line and in primary rat astrocytes. Although further studies would be required to deconvolute the targets involved in LIF induction and to confirm activity of hits in more disease-relevant assays, our results have demonstrated the potential of the phenotypic approach to identify specific and chemically tractable small molecules that trigger the production of LIF in relevant cell lines.


Item Type:Article
Uncontrolled Keywords:leukemia inhibitory factor, phenotypic screening, HTS, multiple sclerosis
Subjects:Medical sciences > Biology
Medical sciences > Biology > Molecular biology
ID Code:43413
Deposited On:16 Jun 2017 16:17
Last Modified:16 Jun 2017 16:17

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