Discovery of a novel DYRK1A Inhibitor with neuroprotective activity by virtual screening and in vitro biological evaluation

Abstract Dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) is implicated in accumulation of amyloid β-protein (Aβ), phosphorylation of Tau proteins, and may eventually cause neurodegenerative diseases. Though many DYRK1A inhibitors have been discovered, there is still no marketed drug targeting DYRK1A. This is partly due to the lack of effective and safe chemotypes; therefore, it is still necessary to identify new classes of DYRK1A inhibitors. By the design of a virtual screening workflow composed of pharmacophore modeling and molecular docking and the following practical application, we identified compound L9, ((Z)-1-(((5-phenyl-1H-pyrazol-4-yl) methylene)-amino)-1H-tetrazol-5-amine), as a moderately active DYRK1A inhibitor (IC50: 1.67 μM). This compound was structurally diverse compared with the known DYRK1A inhibitors, showed a unique binding mode to DYRK1A, and was not toxic to either SH-SY5Y cells or HL-7702 hepatocytes (IC50＞100 μM). Furthermore, compound L9 showed neuroprotective activity by regulating the expression of Aβ and phosphorylation of Tau protein. In conclusion, we have identified a novel DYRK1A inhibitor through virtual screening and in vitro biological evaluation, which holds the promise for further study.