Type-1 diabetes (T1D) is characterized by autoimmune destruction of pancreatic beta cells resulting in decreased insulin production. The secretion of inflammatory cytokines by infiltrating macrophages in the pancreatic islets of Langerhans triggers an intracellular signaling cascade leading to beta-cell apoptosis. The development of small molecules that prevent immune system-mediated death of beta cells may have therapeutic potential to augment traditional insulin replacement therapy for the treatment of T1D. At the Broad Institute, we developed a phenotypic assay using the rat INS-1E beta-cell line to measure cell viability when treated with small molecules in the presence of the cytokines: tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma. Subsequently, a high-throughput screen (HTS) identified several small-molecule �hits� that suppressed beta-cell apoptosis. Here, we report the discovery, medicinal chemistry optimization, and mechanism-of-action studies of diversity-oriented synthesis (DOS)-generated small molecules that protect beta cells from the deleterious effects of cytokines.

Novel small-molecule suppressors of cytokine-induced beta-cell apoptosis for the treatment of type 1 diabetes

245th National Meeting (2013)

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