Type 1 diabetes (T1D) affects millions of people worldwide. Once developed, this chronic, metabolic disease stays with the patient for life. The rate at which T1D is diagnosed is increasing each year (CDC). In T1D, the body is incapable of producing insulin, an important hormone that regulates glucose uptake. Lower production of this hormone results from autoimmune destruction of insulin-producing pancreatic β-cells.
Current methods of treatment involve injection of exogenous insulin, but this does not target the underlying pathophysiology of T1D. As an alternative we seek to synthesize a small molecule that can suppress β-cell apoptosis to restore normal insulin levels. By utilizing diversity-oriented synthesis (DOS), chemical screening methods, and phenotypic assays, we found that the compound BRD0476 was effective in suppressing apoptosis in rat beta cells in the presence of the pro-inflammatory cytokines IFN-γ, IL-β, and TNF-α. Mechanism of action studies revealed that BRD0476 inhibits the IFN-γ induced, STAT1 pathway.
Starting with BRD0476, a diverse selection of analogs was synthesized to increase both the solubility and potency of the molecule. Alcohol and amine derivatives were synthesized using acylation, carbonylation-amination, reductive amination, and Staudinger reduction reactions. Biological activity of these compounds was assessed using a caspase-3 assay to measure the inhibition of apoptosis. Soluble, biologically active compounds may lead to alternative treatment options for type 1 diabetes.
PROJECT: Synthesis of Small Molecule Suppressors of Cytokine-Induced β-Cell Apoptosis
Mentor: Stephen Scully, Chemical Biology Program
"The Broad does science different. Chemistry, biology, genetics, and many other disciplines come together here in ways I did not think possible. This summer I got the chance to work on an amazing project in a setting designed to facilitate great science and push great scientists to become even better. The Summer Research Program in Genomics works to nurture students as young scientists and offers unique opportunities for students to grow as individuals in a supportive community. I would definitely come back to experience it again"