Multistage Screening Reveals 3‑Substituted Indolin-2-one Derivatives as Novel and Isoform-Selective c‑Jun N‑terminal Kinase 3 (JNK3) Inhibitors: Implications to Drug Discovery for Potential Treatment of Neurodegenerative Diseases

Alzheimer’s
disease (AD) is one of the most challenging
diseases around the world with no effective clinical treatment. Previous
studies have suggested c-Jun N-terminal kinase 3 (JNK3) as an attractive
therapeutic target for AD. Herein, we report 3-substituted indolin-2-one
derivatives as the first isoform-selective JNK3 inhibitors by multistage
screening. In this study, comparative structure-based virtual screening
was performed, and J30-8 was identified with a half-maximal
inhibitory concentration of 40 nM, which exhibited over 2500-fold
isoform selectivity and marked kinome-wide selectivity. Further study
indicated that 1 μM J30-8 exhibited neuroprotective
activity in vitro so as to alleviate the spatial memory impairment
in vivo through reducing plaque burden and inhibiting the phosphorylation
of JNKs, Aβ precursor protein, and Tau protein. All of these
indicated J30-8 as proved isoform-selective JNK3 inhibitors
that might serve as a useful tool for further JNK3 studies with AD
as well as for the development of JNK3 inhibitors for the potential
treatment of neurodegenerative diseases.

阿尔茨海默病（Alzheimer’s disease, AD）是全球最具挑战性的疾病之一，目前尚无有效的临床治疗手段。既往研究表明，c-Jun氨基末端激酶3（c-Jun N-terminal kinase 3, JNK3）是极具潜力的AD治疗靶点。本研究通过多阶段筛选，报道了首个亚型选择性JNK3抑制剂——3-取代吲哚啉-2-酮衍生物。本研究开展了基于结构的比较虚拟筛选，最终鉴定得到化合物J30-8，其半数抑制浓度（half-maximal inhibitory concentration）为40 nM，展现出超过2500倍的亚型选择性以及显著的激酶组选择性。进一步研究表明，浓度为1 μM的J30-8在体外具备神经保护活性，同时可通过降低斑块负荷、抑制JNKs、β淀粉样前体蛋白（Aβ precursor protein）及Tau蛋白的磷酸化，在体内缓解空间记忆障碍。上述结果证实，J30-8是一种经过验证的亚型选择性JNK3抑制剂，既可作为开展AD相关JNK3研究的有效工具，也可为靶向JNK3的神经退行性疾病潜在治疗药物的开发提供支撑。