| First Author | Jones Lipinski RA | Year | 2024 |
| Journal | Am J Physiol Regul Integr Comp Physiol | Volume | 326 |
| Issue | 6 | Pages | R515-R527 |
| PubMed ID | 38618911 | Mgi Jnum | J:390815 |
| Mgi Id | MGI:7662775 | Doi | 10.1152/ajpregu.00259.2023 |
| Citation | Jones Lipinski RA, et al. (2024) Zinc-chelating BET bromodomain inhibitors equally target islet endocrine cell types. Am J Physiol Regul Integr Comp Physiol 326(6):R515-R527 |
| abstractText | Inhibition of the bromodomain and extraterminal domain (BET) protein family is a potential strategy to prevent and treat diabetes; however, the clinical use of BET bromodomain inhibitors (BETis) is associated with adverse effects. Here, we explore a strategy for targeting BETis to beta cells by exploiting the high-zinc (Zn(2+)) concentration in beta cells relative to other cell types. We report the synthesis of a novel, Zn(2+)-chelating derivative of the pan-BETi (+)-JQ1, (+)-JQ1-DPA, in which (+)-JQ1 was conjugated to dipicolyl amine (DPA). As controls, we synthesized (+)-JQ1-DBA, a non-Zn(2+)-chelating derivative, and (-)-JQ1-DPA, an inactive enantiomer that chelates Zn(2+). Molecular modeling and biophysical assays showed that (+)-JQ1-DPA and (+)-JQ1-DBA retain potent binding to BET bromodomains in vitro. Cellular assays demonstrated (+)-JQ1-DPA attenuated NF-kB target gene expression in beta cells stimulated with the proinflammatory cytokine interleukin 1beta. To assess beta-cell selectivity, we isolated islets from a mouse model that expresses green fluorescent protein in insulin-positive beta cells and mTomato in insulin-negative cells (non-beta cells). Surprisingly, Zn(2+) chelation did not confer beta-cell selectivity as (+)-JQ1-DPA was equally effective in both beta and alpha cells; however, (+)-JQ1-DPA was less effective in macrophages, a nonendocrine islet cell type. Intriguingly, the non-Zn(2+)-chelating derivative (+)-JQ1-DBA displayed the opposite selectivity, with greater effect in macrophages compared with (+)-JQ1-DPA, suggesting potential as a macrophage-targeting molecule. These findings suggest that Zn(2+)-chelating small molecules confer endocrine cell selectivity rather than beta-cell selectivity in pancreatic islets and provide valuable insights and techniques to assess Zn(2+) chelation as an approach to selectively target small molecules to pancreatic beta cells.NEW & NOTEWORTHY Inhibition of BET bromodomains is a novel potential strategy to prevent and treat diabetes mellitus. However, BET inhibitors have negative side effects. We synthesized a BET inhibitor expected to exploit the high zinc concentration in beta cells to accumulate in beta cells. 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. |
