Small-molecule DYRK1A Inhibitors for β-Cell Regeneration in Diabetes: Structural Insights and Medicinal Chemistry Advances.

Diabetes mellitus results from inadequate pancreatic β-cell mass or function, whereas mature β-cells are generally incapable of spontaneous proliferation. Therefore, promoting β-cell proliferation could be an approach toward diabetes interventions. Over the past decades, dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) has emerged as a key negative regulator of β-cell proliferation via modulating the NFAT signaling pathway and DREAM complex assembly, thereby establishing DYRK1A as a promising therapeutic target for diabetes. In this minireview, we provide an overview of recent progress (2018-2025) in medicinal chemistry toward small-molecule DYRK1A inhibitors for β-cell regeneration. Particular attention is paid to scaffold design, Structure-Activity Relationship (SAR) analysis, and structure-based optimization of representative compounds. We systematically discuss the structural modifications and biological evaluation of natural product-derived scaffolds (such as β-carboline harmine and its analogues, xanthone desmethylbellidifolin) and synthetic scaffolds (including aminopyrazine, 6-azaindole, 1,5- naphthyridine and 1,3,4-thiadiazine), as well as their proliferative effects on human β-cells in vitro and in vivo. Additionally, we highlight medicinal chemistry strategies aimed at improving DYRK1A selectivity, reducing off-target effects, and uncoupling pro-proliferative activity from cytotoxicity. Finally, this review outlines the current challenges and future prospects for the rational design of potent, selective, and β-cell-targeted DYRK1A inhibitors from a medicinal chemistry perspective.