Discovery of Enhancers of the Secretion of Leukemia Inhibitory Factor for the Treatment of Multiple Sclerosis

Abstract

These authors contributed equally to this work.Received Oct 30, 2015, and AbstractMultiple 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 T H 17 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.

Receptor for advanced glycation end-products and World Trade Center particulate induced lung function loss: A case-cohort study and murine model of acute particulate exposure

“…LIF is a cytokine from the IL-6 family that has been shown to promote traditionally inflammatory biological activities including cell proliferation and survival. [ 121 , 122 ] However, recent studies also show its anti-inflammatory properties in the lung and other organs. [ 123 – 125 ]…”

Leukemia inhibitory factor inhibits erythropoietin-induced myelin gene expression in oligodendrocytes

“…Studies in LIF knock-out mice and exogenous LIF administration have highlighted its protective action in many models of demyelination (Nicola & Babon, 2015 ; Davis & Pennypacker, 2018 ; Slaets et al, 2010 ; Emery et al, 2006 ; Marriott et al, 2008 ), suggesting the possible therapeutic use of LIF and LIF inducers in demyelinating diseases, including MS (Slaets et al, 2010 ; Vela et al, 2016 ; Metcalfe, 2018 ).…”

JBS Special Issue: Innovative Screening Methodologies to Identify New Compounds for the Treatment of Central Nervous System Disorders

“…The article by Copmans et al 5 uses the photomotor response of zebrafish and a new behavioral data analysis paradigm to identify phenotypes associated with different classes of neuroactive molecules. Another example of the utility of a phenotypic screen is provided by Vela et al, 6 in which the ability of compounds to enhance production of leukemia inhibitory factor, a cytokine involved in neuroinflammation, is examined in a variety of cell lines. A targeted approach directed at inhibitors of macrophage migration inhibitory factor is described by Zapatero et al 7…”