生物活性

• 描述Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a member of an evolutionarily conserved family of protein kinases that belongs to the CMGC group of kinases, has been studied as a potential cancer therapeutic target for its role in the regulation of cell cycle progression by affecting both tumor suppressors and oncogenesJarhad DB, Mashelkar KK, Kim HR, Noh M, Jeong LS. Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) Inhibitors as Potential Therapeutics. J Med Chem. 2018;61(22):9791–9810.https://pubmed.ncbi.nlm.nih.gov/29985601/. Glycogen synthase kinase 3 (GSK-3) plays an important role in the pathogenesis of numerous disorders, affecting the central nervous system (CNS) encompassing both neuroinflammation and neurodegenerative diseases. Glycogen synthase kinase 3 beta (GSK-3β) is one of the GSK-3 isomersGolpich M, Amini E, Hemmati F, et al. Glycogen synthase kinase-3 beta (GSK-3β) signaling: Implications for Parkinson's disease. Pharmacol Res. 2015;97:16–26. https://pubmed.ncbi.nlm.nih.gov/25829335/. GNF4877 is a potent DYRK1A and GSK3β inhibitor with IC50s of 6 nM and 16 nM, respectively. GNF4877 stimulates proliferation of reversibly immortalized mouse beta (R7T1) cells, with EC₅₀ (half-maximal effective concentration) of 0.66 μM. Mouse model of type 1 diabetes (T1D) treated with GNF4877 (oral, 50 mg/kg twice daily) showed dramatically improved glucose tolerance, increased insulin staining, proliferating β-cells, β-cell mass (∼1.5 fold), insulin content (∼2 fold), and improved oral glucose tolerance, compared to vehicle-treated groupShen W, Taylor B, Jin Q, et al. Inhibition of DYRK1A and GSK3B induces human β-cell proliferation. Nat Commun. 2015;6:8372. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639830/.