Faculty Collaboration Database

Zinc-chelating BET bromodomain inhibitors equally target islet endocrine cell types. Am J Physiol Regul Integr Comp Physiol 2024 Jun 01;326(6):R515-R527

Date

04/15/2024

Pubmed ID

38618911

Pubmed Central ID

PMC11381023

DOI

10.1152/ajpregu.00259.2023

Scopus ID

2-s2.0-85194976711 (requires institutional sign-in at Scopus site)

Abstract

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 β cells by exploiting the high-zinc (Zn²⁺) concentration in β cells relative to other cell types. We report the synthesis of a novel, Zn²⁺-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-Zn²⁺-chelating derivative, and (-)-JQ1-DPA, an inactive enantiomer that chelates Zn²⁺. 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-ĸB target gene expression in β cells stimulated with the proinflammatory cytokine interleukin 1β. To assess β-cell selectivity, we isolated islets from a mouse model that expresses green fluorescent protein in insulin-positive β cells and mTomato in insulin-negative cells (non-β cells). Surprisingly, Zn²⁺ chelation did not confer β-cell selectivity as (+)-JQ1-DPA was equally effective in both β and α cells; however, (+)-JQ1-DPA was less effective in macrophages, a nonendocrine islet cell type. Intriguingly, the non-Zn²⁺-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 Zn²⁺-chelating small molecules confer endocrine cell selectivity rather than β-cell selectivity in pancreatic islets and provide valuable insights and techniques to assess Zn²⁺ chelation as an approach to selectively target small molecules to pancreatic β 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 β cells to accumulate in β 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.

Author List

Jones Lipinski RA, Stancill JS, Nuñez R, Wynia-Smith SL, Sprague DJ, Nord JA, Bird A, Corbett JA, Smith BC

Authors

John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of Wisconsin
Rachel Jones Lipinski Research Scientist I in the Biochemistry department at Medical College of Wisconsin
Brian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Azepines
Chelating Agents
Glucagon-Secreting Cells
Humans
Insulin-Secreting Cells
Male
Mice
Mice, Inbred C57BL
Nuclear Proteins
Transcription Factors
Triazoles
Zinc