We are interested in factors controlling gene transcription, specifically epigenetic regulatory proteins. This includes the bromodomain family of epigenetic “reader” proteins and the sirtuin family of epigenetic “eraser” proteins, each of which interact with acylated lysine residues. Using drug-like chemical probes and targeted therapies, we dissect the roles of such proteins in autoimmune diabetes onset and progression.
ZINC-CHELATING BET BROMODOMAIN INHIBITORS EQUALLY TARGET ISLET ENDOCRINE CELL TYPES
Inhibition of BET bromodomains is a novel potential strategy to prevent and treat diabetes mellitus. However, BET inhibitors have been shown to have numerous off-target systemic side effects. We synthesized a BET inhibitor expected to exploit the high zinc concentration in β cells to accumulate in β cells (Jones Lipinski et al, 2024). We show our inhibitor targeted pancreatic endocrine cells; however, it was less effective in immune cells. A control inhibitor showed the opposite effect. These findings help us understand how to target specific cells in diabetes treatment.
BET BROMODOMAIN INHIBITORS DISRUPT A BRD4-p65 INTERACTION
Chronic inflammation in pancreatic islets is a key driver of damage that leads to eventual onset of type I autoimmune diabetes. We investigated the ability of BET bromodomain inhibitors to reduce pancreatic β-cell responsiveness to the proinflammatory cytokine IL-1β (Nord et al 2022). Indeed, this inhibition attenuated inflammatory mediator gene NOS2, consistent with inhibition of NF-kB. We used selective inhibitors of the first and second bromodomains of BRD4 and showed only the first bromodomain was necessary for interaction of the NF-kB p65 subunit with BRD4. This is the first study illustrating the therapeutic potential for specific bromodomain-targeted inhibitors in autoimmune diabetes.
REFERENCES
Jones Lipinski RA, Stancill JS, Nuñez R, Wynia-Smith SL, Sprague DJ, Nord JA, Bird A, Corbett JA, Smith BC. Zinc-chelating BET bromodomain inhibitors equally target islet endocrine cell types. American Journal of Physiology: Regulatory, Integrative, and Comparative Physiology. (2024). doi: 10.1152/ajpregu.00259.2023. PMID: 38618911
Nord JA, Wynia-Smith SL, Gehant AL, Jones Lipinski RA, Naatz A, Rioja I, Kumar Prinja R, Corbett JA, Smith BC. N-terminal BET bromodomain inhibitors disrupt a BRD4-p65 interaction and reduce inducible nitric oxide synthase transcription in pancreatic ß-cells. Frontiers in Endocrinology. 2022. DOI: 10.3389/fendo.2022.923925.
