Discovery of ZJCK-6-46: A Potent, Selective, and Orally Available Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A Inhibitor for the Treatment of Alzheimer’s Disease

作者：Huanhua Chen, Xudong Gao, Xinzhu Li, Chong Yu, Wenwu Liu, Jingsong Qiu, Wenjie Liu, Hefeng Geng, Fangyuan Zheng, Hao Gong, Zihua Xu, Jing‐Ming Jia, Qingchun Zhao · 发表于：Journal of Medicinal Chemistry · 年份：2024 · DOI：10.1021/acs.jmedchem.4c00483 · 被引用次数：23 · 研究领域：Histone Deacetylase Inhibitors Research、Protein Tyrosine Phosphatases、Signaling Pathways in Disease

Targeting dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has been verified to regulate the progression of tau pathology as a promising treatment for Alzheimer’s disease (AD), while the research progress on DYRK1A inhibitors seemed to be in a bottleneck period. In this work, we identified 32 ( ZJCK-6-46 ) as the most potential DYRK1A inhibitor (IC 50 = 0.68 nM) through rational design, systematic structural optimization, and comprehensive evaluation. Compound 32 exhibited acceptable in vitro absorption, distribution, metabolism, and excretion (ADME) properties and significantly reduced the expression of p-Tau Thr212 in Tau (P301L) 293T cells and SH-SY5Y cells. Moreover, compound 32 showed favorable bioavailability, blood–brain barrier (BBB) permeability, and the potential of ameliorating cognitive dysfunction by obviously reducing the expression of phosphorylated tau and neuronal loss in vivo, which was deserved as a valuable molecular tool to reveal the role of DYRK1A in the pathogenesis of AD and to further promote the development of anti-AD drugs.