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Identification of Small Molecule Inhibitors that Suppress Cytokine-Induced Apoptosis in Human Pancreatic Islet Cells

Publication TypeJournal Article
Year of Publication2012
AuthorsFaloon, PW, Chou, DHC, Forbeck, EM, Walpita, D, Morgan, B, Buhrlage, S, Ting, A, Perez, J, MacPherson, LJ, Duvall, JR, Dandapani, S, Marcaurelle, LA, Munoz, B, Palmer, M, Foley, M, Wagner, B, Schreiber, SL
Date Published2012/01/09

Type 1 diabetes is caused by autoimmune destruction of insulin-producing beta cells in the pancreas. In this process, beta-cell apoptosis involves multiple signaling cascades stimulated by interleukin-1β (IL-1β), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). These pathways result in decreased pancreatic beta-cell numbers that lead to the disease phenotype. Most of the compounds described in the literature protect cells from a single facet of cytokine treatment but do not provide wide-ranging protection from apoptosis nor do they restore insulin secretion. The goal of this project was to identify and to optimize small molecules that can prevent cytokine-induced pancreatic beta-cell apoptosis. To achieve this goal, we completed a screen of 339,000 compounds in rat INS-1E insulinoma cells treated with IL-1β, IFN-γ, and TNF-α. As a result, we identified MLS003179189, a member of a novel diversity-oriented synthesis (DOS) library with stereochemical diversity and complexity akin to naturally occurring small molecules. MLS003179189 contains 3 stereocenters and was the only stereoisomer (out of eight possible stereoisomers) to show activity in the primary assay for cell viability. About 50 analogs of the active stereoisomer were synthesized and tested, leading to a superior probe candidate (ML187). In studies with dissociated human primary pancreatic islets, (ML187) improved cell viability, decreased caspase activation, and improved insulin production. These data suggest that a consistent mechanism of action exists in both rat and human cells and that the probe (ML187) is a first-in-class probe for Type I diabetes that both protects against destruction of beta cells and restores function.