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.
Huanhua ChenXudong GaoXinzhu LiChong YuWenwu LiuJingsong QiuWenjie LiuHefeng GengFangyuan ZhengHao GongZihua XuJingming JiaQing-Chun ZhaoPublished in: Journal of medicinal chemistry (2024)
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.
Keyphrases
- blood brain barrier
- cerebrospinal fluid
- protein kinase
- poor prognosis
- cerebral ischemia
- induced apoptosis
- cognitive decline
- transcription factor
- small molecule
- gene expression
- binding protein
- dna methylation
- endothelial cells
- human health
- long non coding rna
- high throughput
- risk assessment
- combination therapy
- climate change
- signaling pathway
- replacement therapy
- structural basis
- anti inflammatory
- subarachnoid hemorrhage
- smoking cessation