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The pathogenesis of diabetes mellitus is characterized by insulin resistance and islet β-cell dysfunction. Up to now, the focus of diabetes treatment has been to control blood glucose to prevent diabetic complications. There is an urgent need to develop a therapeutic approach to restore the mass and function of β-cells. Although exogenous islet cell transplantation has been used to help patients control blood glucose, it is costly and has very narrow application scenario. So far, small molecules have been reported to stimulate β-cell proliferation and expand β-cell mass, increasing insulin secretion. Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) inhibitors can induce human β-cell proliferation in vitro and in vivo, and show great potential in the field of diabetes therapeutics. From this perspective, we elaborated on the mechanism by which DYRK1A inhibitors regulate the proliferation of pancreatic β-cells, and summarized several effective natural DYRK1A inhibitors, hoping to provide clues for subsequent structural optimization and drug development in the future. [ABSTRACT FROM AUTHOR]

The pathogenesis of diabetes mellitus is characterized by insulin resistance and islet β-cell dysfunction. Up to now, the focus of diabetes treatment has been to control blood glucose to prevent diabetic complications. There is an urgent need to develop a therapeutic approach to restore the mass and function of β-cells. Although exogenous islet cell transplantation has been used to help patients control blood glucose, it is costly and has very narrow application scenario. So far, small molecules have been reported to stimulate β-cell proliferation and expand β-cell mass, increasing insulin secretion. Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) inhibitors can induce human β-cell proliferation in vitro and in vivo, and show great potential in the field of diabetes therapeutics. From this perspective, we elaborated on the mechanism by which DYRK1A inhibitors regulate the proliferation of pancreatic β-cells, and summarized several effective natural DYRK1A inhibitors, hoping to provide clues for subsequent structural optimization and drug development in the future.

Recently, we have shown that harmine induces β-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. We explore structure–activity relationships of the 7-position of harmine for both DYRK1A kinase inhibition and β-cell proliferation based on our related previous structure–activity relationship studies of harmine in the context of diabetes and β-cell specific targeting strategies. 33 harmine analogs of the 7-position substituent were synthesized and evaluated for biological activity. Two novel inhibitors were identified which showed DYRK1A inhibition and human β-cell proliferation capability. The DYRK1A inhibitor, compound 1-2b, induced β-cell proliferation half that of harmine at three times higher concentration. From these studies we can draw the inference that 7-position modification is limited for further harmine optimization focused on β-cell proliferation and cell-specific targeting approach for diabetes therapeutics.

Abstract The Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) is an enzyme that has been implicated as an important drug target in various therapeutic areas, including neurological disorders (Down syndrome, Alzheimer's disease), oncology, and diabetes (pancreatic β-cell expansion). Current small molecule DYRK1A inhibitors are ATP-competitive inhibitors that bind to the kinase in an active conformation. As a result, these inhibitors are promiscuous, resulting in pharmacological side effects that limit their therapeutic applications. None are in clinical trials at this time. In order to identify a new DYRK1A inhibitor scaffold, we constructed a homology model of DYRK1A in an inactive, DFG-out conformation. Virtual screening of 2.2 million lead-like compounds from the ZINC database, followed by in vitro testing of selected 68 compounds revealed 8 hits representing 5 different chemical classes. We chose to focus on one of the hits from the computational screen, thiadiazine 1 which was found to inhibit DYRK1A with IC 50 of 9.41 μM (K d = 7.3 μM). Optimization of the hit compound 1, using structure-activity relationship (SAR) analysis and in vitro testing led to the identification of potent thiadiazine analogs with significantly improved binding as compared to the initial hit (K d = 71–185 nM). Compound 3–5 induced human β-cell proliferation at 5 μM while showing selectivity for DYRK1A over DYRK1B and DYRK2 at 10 μM. This newly developed DYRK1A inhibitor scaffold with unique kinase selectivity profiles has potential to be further optimized as novel therapeutics for diabetes. Graphical abstract Image 1 Highlights • Homology model of DYRK1A in the inactive, DFG-out conformation was developed using DFGmodel protocol. • Virtual screen of the ZINC database and in vitro testing revealed hit thiadiazine 1 with DYRK1A K d = 7.3 µM. • Hit-to-lead SAR study was carried out by modifications at the 2-amino position to improve hit DYRK1A binding potency. • 27 analogues synthesized to identify two compounds with significantly improved binding to DYRK1A (K d = 71–185 nM). • New lead compound 3–5 induced human β-cell proliferation at 5 µM and improved selectivity for closely related kinases. [ABSTRACT FROM AUTHOR]

Abstract: Individuals with Down syndrome (DS) suffer from mental retardation. Overexpression and the resulting increased specific activity of Dyrk1A kinase located on chromosome 21 cause a learning and memory deficit in Dyrk1A transgenic mice. To search for therapeutic agents with Dyrk1A inhibition activity, previously we obtained HCD160 as a new hit compound for Dyrk1A inhibition. In the present study, we synthesized 34 HCD160 derivatives to investigate the quantitative structure–activity relationship (QSAR). This analysis could provide important information for novel drug discovery for treatment of DS related learning and memory deficits. [Copyright &y& Elsevier]

Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) is a conserved protein kinase that plays essential roles in various biological processes. It is located in the region q22.2 of chromosome 21, which is involved in the pathogenesis of Down syndrome (DS). Moreover, DYRK1A has been shown to promote the accumulation of amyloid beta (Aβ) peptides leading to gradual Tau hyperphosphorylation, which contributes to neurodegeneration. Additionally, alterations in the DRK1A expression are also associated with cancer and diabetes. Recent years have witnessed an explosive increase in the development of DYRK1A inhibitors. A variety of novel DYRK1A inhibitors have been reported as potential treatments for human diseases. In this review, the latest therapeutic potential of DYRK1A for different diseases and the novel DYRK1A inhibitors discoveries are summarized, guiding future inhibitor development and structural optimization. [Display omitted] • Inhibition of DYRK1A is crucial for some severe diseases. • Summary of the latest research progress of DYRK1A inhibitors. • Insight into recent advances in function of DYRK1A. • Presenting the SAR of DYRK1A inhibitors for potential therapy. • Guiding for future drug modification and design of DYRK1A inhibitors. [ABSTRACT FROM AUTHOR]

Recently, we have shown that harmine induces β-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. We explore structure–activity relationships of the 7-position of harmine for both DYRK1A kinase inhibition and β-cell proliferation based on our related previous structure–activity relationship studies of harmine in the context of diabetes and β-cell specific targeting strategies. 33 harmine analogs of the 7-position substituent were synthesized and evaluated for biological activity. Two novel inhibitors were identified which showed DYRK1A inhibition and human β-cell proliferation capability. The DYRK1A inhibitor, compound 1-2b, induced β-cell proliferation half that of harmine at three times higher concentration. From these studies we can draw the inference that 7-position modification is limited for further harmine optimization focused on β-cell proliferation and cell-specific targeting approach for diabetes therapeutics. [ABSTRACT FROM AUTHOR]

Protein kinases play an indispensable role in signaling pathways that regulate tumor cell functions, which represent potent therapeutic targets in cancers. Dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) as a serine/threonine kinase has recently been reported to be upregulated in pancreatic ductal adenocarcinoma (PDAC) and show protumorigenic effect. By activity-guided phytochemical investigation of the extracts from Glycyrrhiza uralensis Fisch, we expect to find the effective constituents that can suppress pancreatic cancer cell proliferation and/or induce cells apoptotic by inhibiting DYRK1A. Eight isopentenyl-substituted compounds (1 – 8), including four coumarins (1 – 4), one benzofuran (5), and three flavonoids (6 – 8), were isolated and identified from G. uralensis Fisch. Among them, licocoumarone (LC, 5) showed effective inhibitory activity against DYRK1A with an IC 50 value of 12.56 μM. Molecular docking analysis suggested that LC completely occupied the whole pocket of DYRK1A and formed obvious hydrophobic interactions and hydrogen bonds with DYRK1A residues. Further in vitro validation, including Microscale Thermophoresis (MST) and drug affinity responsive target stability (DARTS) techniques, demonstrated the specific combining capacity of LC to DYRK1A. Meanwhile, LC induced significant cytotoxicity against DYRK1A-overexpressing BxPC-3 cells with an IC 50 value of 50.77 μM. Mechanism studies revealed that LC reduced c-MET protein level by inhibiting DYRK1A. These findings provide preliminary evidences that LC as a natural DYRK1A inhibitor suppresses human pancreatic adenocarcinoma BxPC-3 cell proliferation and induces cell apoptotic, which might present new options and possibilities for targeted therapies in pancreatic cancer therapy. Image 1 • Licocoumarone potentially targets to DYRK1A revealed by molecular docking. • The binding affinity to DYRK1A was validated by MST and DARTS experiments. • Licocoumarone suppressed BxPC-3 cell proliferation by inhibiting DYRK1A in vitro. [ABSTRACT FROM AUTHOR]