Discovery of Novel Indazole Chemotypes as Isoform-Selective JNK3 Inhibitors for the Treatment of Parkinson’s Disease

Abstract

c-Jun N-terminal kinases (JNKs) are involved in the pathogenesis of various diseases. In particular, JNK3 and not JNK1/2 is primarily expressed in the brain and plays a key role in mediating neurodegenerative diseases like Parkinson's disease (PD). Due to the sequence similarity of JNK isoforms, developing isoform-selective JNK3 inhibitors to evaluate their biological functions and therapeutic potential in PD has become a challenge. Herein, docking-based virtual screening and structure−activity relationship studies identified 25c with excellent inhibitory activity against JNK3 (IC 50 = 85.21 nM) and exhibited an over 100-fold isoform selectivity for JNK3 over JNK1/2 and remarkable kinase selectivity. 25c showed neuroprotective effects on in vitro and in vivo PD models by selectively inhibiting JNK3. Meanwhile, 25c showed an ideal blood−brain barrier permeability and low toxicity. Overall, this study provided a valuable molecular tool for investigating the role of JNK3 in PD and a solid foundation for developing JNK3-targeted drugs in PD treatment.

Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS Generation in Breast Cancer Cells

“…According to X-ray crystallography, the indazole-aminopyrimidine compound binds to JNK1b (PDB: 4HYU) and interacted via two hydrogen bonds with the amino acid backbones of the hinge region [8]. A co-crystal structure of JNK3 (PDB: 3KVX) and the aminopyridine ligand revealed that it was positioned within the adenosine-binding region, and the morpholino substituent was positioned within the hydrophilic sugar pocket [9]. It was also observed in a co-crystal structure of JNK3 (PDB: 4Y5H) that two hydrogen bonds with Met149 were formed at the adenine-binding site [10].…”

Smart-Phone-Assisted Optical Biosensors Based on Silk-Fibroin-Decorated Reduced Graphene Oxide Quantum Dots for Fluorescent Turn-On Recognition of l-Dopa

“…Parkinson’s disease is the second most prevalent debilitating neurological disorder, affecting 3% of the worldwide population over the age of 65. , With aging of the population, a steady and irreversible depletion of dopaminergic neurons in substantia nigra pars compacta leads to an imbalance in the concentration of dopamine in the striatum, and therefore, the accurate management of Parkinson’s disease becomes a challenging task for neurologists. ,− The cause of PD is multifactorial involving different mechanistic pathways such as oxidative stress, neuroinflammation, apoptosis, mitochondrial dysfunction, and so forth . Usually, Parkinson’s patients experience a variety of motor symptoms owing to the brain’s dopamine depletion, including hyperactivity disorder, schizophrenia, static tremor, flexed posture, freezing of gait, rigidity, and so forth …”

Novel Tryptanthrin Derivatives with Selectivity as c–Jun N–Terminal Kinase (JNK) 3 Inhibitors

“…More than 100 JNK inhibitors have been identified, with some even evaluated in clinical trials, yet fewer than ten JNK3-selective inhibitors have been reported [ 44 , 45 , 46 , 47 ]. Tryptanthrin (TRYP) (indolo[2,1- b ]quinazolin-6,12-dione) is an alkaloid that can be isolated from higher plants and several marine organisms (for a review, see [ 48 ]).…”