title: Discovery of Enhancers of the Secretion of Leukemia Inhibitory Factor for the Treatment of Multiple Sclerosis.
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.
authors.affiliation: Centro de Investigación Básica, GSK, Tres Cantos, Madrid, Spain Laura.2.vela@gsk.com.
authors.forename: Laura
authors.initials: L
authors.lastname: Vela
authors.affiliation: Centro de Investigación Básica, GSK, Tres Cantos, Madrid, Spain.
authors.forename: Iván
authors.initials: I
authors.lastname: Caballero
authors.affiliation: GSK (China) R&D Company Limited, Pudong, Shanghai, China.
authors.forename: Leiping
authors.initials: L
authors.lastname: Fang
authors.affiliation: GSK (China) R&D Company Limited, Pudong, Shanghai, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Centro de Investigación Básica, GSK, Tres Cantos, Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Ramón
authors.affiliation: Centro de Investigación Básica, GSK, Tres Cantos, Madrid, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Díez
authors.affiliation: Centro de Investigación Básica, GSK, Tres Cantos, Madrid, Spain.
authors.forename: Maite
authors.initials: M
authors.lastname: de Los Frailes
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002490:Central Nervous System / Q000187:drug effects; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D053605:Leukemia Inhibitory Factor / Q000235:genetics*; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects; D051381:Rats; D054852:Small Molecule Libraries / Q000302:isolation & purification / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects; D058504:Th17 Cells / Q000187:drug effects
chemical_list: C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D054852:Small Molecule Libraries
keywords: HTS; leukemia inhibitory factor; multiple sclerosis; phenotypic screening