Islets of Langerhans are a heterogeneous mixture of endocrine (hormone-secreting) and exocrine cells in the mammalian pancreas. Pancreatic β-cells are the most abundant islet cell-type and maintain glucose homeostasis by secreting insulin in response to increased blood glucose concentrations. Type 1 diabetes (T1D), for which there is no cure, is characterized by the autoimmune destruction of β-cells. The bromodomain and extra-terminal domain (BET) family of epigenetic reader proteins have emerged as novel drug targets to prevent T1D. However, current BET bromodomain inhibitors (BETi) are associated with adverse, off-target effects in clinical trials primarily for cancer indications. Any cure for T1D would be widely used in a pediatric patient population so avoiding off-target effects is imperative. We propose to ameliorate negative effects of BET bromodomain inhibition by targeting BETi to pancreatic β-cells. Here, we exploited the high abundance of glucose transporters on the β-cell surface relative to other cells in the pancreas and conjugated a BETi to glucosamine (GlcN). BETi attenuate gene transcription induced by the pro-inflammatory cytokine IL-1β in the NF-κB signaling. Moreover, GlcN also inhibits gene production in the NF-κB pathway; thus, we hypothesized that our dual BETi-GlcN would have increased efficacy as an anti-inflammatory agent. We synthesized a novel, GlcN-based analogue of JQ1, [JQ1-GlcN], in which the BETi JQ1 was conjugated to GlcN. Molecular modeling and biophysical assays showed that JQ1-GlcN retains binding to both bromodomains of BRD4 <i>in vitro.</i> JQ1-GlcN is selectively active in cell-based and primary rat islet models of T1D. In summary, we developed a novel chemical probe and pharmacological agent selective for pancreatic endocrine cells to harness the full potential of BETi both to mechanistically study the roles of BET bromodomains in the pathophysiology of T1D and selectively target BET proteins in β-cells as a potential therapy to prevent or treat T1D.

Dual glucosamine-BET bromodomain inhibitor acts cooperatively to inhibit transcription of NF-κB target genes in pancreatic β-cells

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ACS Fall 2022

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