Kim Hyejin, Park Haebeen, Jun Joonhong, Moon Jihyun, Oh Jooyoung, Bhujbal Swapnil P, Hah Jung-Mi
Department of Pharmacy, Institute of Pharmaceutical Science and Technology, College of Pharmacy, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do, 15588, Republic of Korea.
Department of Pharmacy, Institute of Pharmaceutical Science and Technology, College of Pharmacy, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do, 15588, Republic of Korea.
Eur J Med Chem. 2025 Mar 5;285:117209. doi: 10.1016/j.ejmech.2024.117209. Epub 2025 Jan 3.
JNK3, a brain-specific stress-activated protein kinase, plays a critical role in Alzheimer's disease pathogenesis through phosphorylation of Tau and APP. This study aimed to develop selective JNK3 inhibitors based on a pyrazole scaffold, focusing on (E)-1-(2-aminopyrimidin-4-yl)-4-styryl-1H-pyrazole-3-carboxamide derivatives. Through systematic structural modifications and extensive SAR analysis, we identified compounds 24a and 26a as highly potent JNK3 inhibitors, with IC values of 12 and 19 nM, respectively. Especially, 24a revealed its potent and selective inhibition of JNK3, coupled with inhibition of the GSK3α/β kinases involved in Tau phosphorylation. In vitro studies revealed significant neuroprotective effects against Aβ-induced toxicity in primary neuronal cells and western blot analyses confirmed the compounds' ability to mitigate Aβ-induced c-Jun and APP phosphorylation, suggesting a multi-faceted approach to neuroprotection. Docking studies validated the retention of optimal interactions within the JNK3 binding pocket. Importantly, BBB PAMPA assays and ADME predictions indicated favorable blood-brain barrier permeability and pharmacokinetic profiles for the lead compounds. These findings represent a significant advancement in the development of selective JNK3 inhibitors, providing a strong foundation for further preclinical development of potential Alzheimer's disease therapeutics.
JNK3是一种大脑特异性应激激活蛋白激酶，通过对Tau蛋白和淀粉样前体蛋白（APP）进行磷酸化，在阿尔茨海默病发病机制中发挥关键作用。本研究旨在开发基于吡唑骨架的选择性JNK3抑制剂，重点研究（E）-1-（2-氨基嘧啶-4-基）-4-苯乙烯基-1H-吡唑-3-甲酰胺衍生物。通过系统的结构修饰和广泛的构效关系（SAR）分析，我们确定化合物24a和26a为高效的JNK3抑制剂，其IC值分别为12和19 nM。特别是，24a显示出对JNK3的强效和选择性抑制作用，同时抑制参与Tau蛋白磷酸化的糖原合成酶激酶3α/β（GSK3α/β）。体外研究表明，其对原代神经元细胞中Aβ诱导的毒性具有显著的神经保护作用，蛋白质免疫印迹分析证实这些化合物能够减轻Aβ诱导的c-Jun和APP磷酸化，提示其具有多方面的神经保护作用。分子对接研究验证了JNK3结合口袋内最佳相互作用的保留。重要的是，血脑屏障（BBB）平行人工膜渗透测定（PAMPA）和药物代谢动力学预测表明，先导化合物具有良好的血脑屏障通透性和药代动力学特征。这些发现代表了选择性JNK3抑制剂开发方面的重大进展，为潜在的阿尔茨海默病治疗药物的进一步临床前开发提供了坚实的基础。
