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

Haishan Zhou1, Yan Wang2, Juan Bai3

  • 1College of Pharmaceutical Science, Anhui Xinhua University, Hefei 230088, China.

Mini Reviews in Medicinal Chemistry
|August 24, 2026
PubMed

Insights

Targeting dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) with small molecules can promote pancreatic beta-cell regeneration. This review highlights medicinal chemistry advances in developing DYRK1A inhibitors for diabetes treatment.

Area of Science:

  • Medicinal Chemistry
  • Endocrinology
  • Molecular Biology

Background:

  • Diabetes mellitus stems from insufficient pancreatic beta-cell mass or function.
  • Mature beta-cells typically do not proliferate spontaneously.
  • Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) inhibits beta-cell proliferation by regulating NFAT signaling and DREAM complex assembly.

Purpose of the Study:

  • To review recent medicinal chemistry progress (2018-2025) in developing small-molecule DYRK1A inhibitors for beta-cell regeneration.
  • To focus on scaffold design, SAR analysis, and structure-based optimization of these inhibitors.
  • To discuss strategies for enhancing DYRK1A inhibitor selectivity, reducing off-target effects, and improving safety profiles.

Main Methods:

  • Systematic review of recent literature (2018-2025) on DYRK1A inhibitors.
  • Analysis of scaffold modifications (natural product-derived and synthetic) and their structure-activity relationships.
  • Evaluation of in vitro and in vivo proliferative effects on human beta-cells.

Main Results:

  • Exploration of various scaffolds, including beta-carboline harmine, xanthone desmethylbellidifolin, aminopyrazine, 6-azaindole, 1,5-naphthyridine, and 1,3,4-thiadiazine.
  • Demonstration of beta-cell proliferative effects of optimized DYRK1A inhibitors.
  • Identification of strategies to improve inhibitor selectivity and reduce cytotoxicity.

Conclusions:

  • DYRK1A is a viable therapeutic target for beta-cell regeneration in diabetes.
  • Medicinal chemistry efforts have yielded promising small-molecule inhibitors with potential for diabetes intervention.
  • Further research is needed for rational design of potent, selective, and beta-cell-targeted DYRK1A inhibitors.
Keywords:
DYRK1A inhibitorsdiabeteskinasemedicinal chemistryproliferationsmall moleculeβ-cell

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