Discovery of a novel chemotype as DYRK1A inhibitors against Alzheimer's disease: Computational modeling and biological evaluation.

Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) plays an essential role in Tau and Aβ pathology closely related to Alzheimer's disease (AD). Accumulative evidence has demonstrated DYRK1A inhibition is able to reduce the pathological features of AD. Nevertheless, there is no approved DYRK1A inhibitor for clinical use as anti-AD therapy. This is somewhat due to the lack of effective and safe chemotypes of DYRK1A inhibitors. To address this issue, we carried out in silico screening, in vitro assays and in vivo efficacy evaluation with the aim to discover a new class of DYRK1A inhibitors for potential treatment of AD. By in silico screening, we selected and purchased 16 potential DYRK1A inhibitors from the Specs chemical library. Among them, compound Q17 (Specs ID: AO-476/40829177) potently inhibited DYRK1A. The hydrogen bonds between compound Q17 and two amino acid residues named GLU239 and LYS188, were uncovered by molecular docking and molecular dynamics simulation. The cell-based assays showed that compound Q17 could protect the SH-SY5Y human neuroblastoma cell line from okadaic acid (OA)-induced injury by targeting DYRK1A. More importantly, compound Q17 significantly improved cognitive dysfunction of 3 × Tg-AD mice, ameliorated pathological changes, and attenuated Tau hyperphosphorylation as well as Aβ deposition. In summary, our computational modeling strategy is effective to identify novel chemotypes of DYRK1A inhibitors with great potential to treat AD, and the identified compound Q17 in this study is worthy of further study.