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.