Carbamate JNK3 Inhibitors Show Promise as Effective Treatments for Alzheimer’s Disease: In Vivo Studies on Mouse Models

Self Cite

Owing to the dysregulation of protein kinase activity in various diseases such as cancer and autoimmune, cardiovascular, neurodegenerative, and inflammatory conditions, the protein kinase family has emerged as a crucial drug target in the 21st century. Notably, many kinases have been targeted to address cancer and neurodegenerative diseases using conventional ATP-mimicking kinase inhibitors. Likewise, irreversible covalent inhibitors have also been developed for different types of cancer. The application of covalent modification to target proteins has led to significant advancements in the treatment of cancer. However, while covalent drugs have significantly impacted medical treatment, their potential for neurodegenerative diseases remains largely unexplored. Neurodegenerative diseases present significant risks to brain function, leading to progressive deterioration in sensory, motor, and cognitive abilities. Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), and multiple sclerosis (MS) are among the various examples of such disorders. Numerous research groups have already reported insights through reviews and research articles on FDA-approved covalent inhibitors, revealing their mechanisms and the specific covalent warheads that preferentially interact with particular amino acid residues in intricate detail. Hence, in this review, we aim to provide a concise summary of these critical topics. This summary endeavors to guide medicinal chemists in their quest to design covalent inhibitors for protein kinases, specifically targeting neurodegenerative diseases.

Section: Types Of Covalent Inhibitorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An Innovative Approach to Address Neurodegenerative Diseases through Kinase-Targeted Therapies: Potential for Designing Covalent Inhibitors

Bhujbal,

Hah

2023

Self Cite

“…Synaptic dysfunction and spine loss have been reported to be pharmacologically reversible, opening new therapeutic directions in brain diseases. JNK3 could be used as a disease biomarker as it is detectable at the peripheral level, allowing an early diagnosis of neurodegenerative and neurodevelopment diseases in a still prodromal stage [ 37 , 38 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

An Intriguing Purview on the Design of Macrocyclic Inhibitors for Unexplored Protein Kinases through Their Binding Site Comparison

Bhujbal

Hah

2023

Self Cite

Kinases play an important role in regulating various intracellular signaling pathways that control cell proliferation, differentiation, survival, and other cellular processes, and their deregulation causes more than 400 diseases. Consequently, macrocyclization can be considered a noteworthy approach to developing new therapeutic agents for human diseases. Macrocyclization has emerged as an effective drug discovery strategy over the past decade to improve target selectivity and potency of small molecules. Small compounds with linear structures upon macrocyclization can lead to changes in their physicochemical and biological properties by firmly reducing conformational flexibility. A number of distinct protein kinases exhibit similar binding sites. Comparison of protein binding sites provides crucial insights for drug discovery and development. Binding site similarities are helpful in understanding polypharmacology, identifying potential off-targets, and repurposing known drugs. In this review, we focused on comparing the binding sites of those kinases for which macrocyclic inhibitors are available/studied so far. Furthermore, we calculated the volume of the binding site pocket for each targeted kinase and then compared it with the binding site pocket of the kinase for which only acyclic inhibitors were designed to date. Our review and analysis of several explored kinases might be useful in targeting new protein kinases for macrocyclic drug discovery.

“…Upon activation, JNKs can interact with the pathway's final effectors, phosphorylate transcription factors, such as the transcription factor activator protein-1 (AP1) family proteins, c-JUN, activating transcription factors (ATF), and (ETS Like-1 protein) Elk1 [1]. Based on knockout experiments and its specific tissue expression, JNK3 has emerged as a promising target for potential treatments of neuroinflammation and neurodegenerative disorders like Huntington's disease [2][3][4], Parkinson's disease [5], and Alzheimer's disease [6][7][8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Identification of Potential JNK3 Inhibitors: A Combined Approach Using Molecular Docking and Deep Learning-Based Virtual Screening

Yao,

Shen,

Shen

et al. 2023

JNK3, a member of the MAPK family, plays a pivotal role in mediating cellular responses to stress signals, with its activation implicated in a myriad of inflammatory conditions. While JNK3 holds promise as a therapeutic target for neurodegenerative disorders such as Huntington’s, Parkinson’s, and Alzheimer’s diseases, there remains a gap in the market for effective JNK3 inhibitors. Despite some pan-JNK inhibitors reaching clinical trials, no JNK-targeted therapies have achieved market approval. To bridge this gap, our study introduces a sophisticated virtual screening approach. We begin with an energy-based screening, subsequently integrating a variety of rescoring techniques. These encompass glide docking scores, MM/GBSA, and artificial scoring mechanisms such as DeepDock and advanced Graph Neural Networks. This virtual screening workflow is designed to evaluate and identify potential small-molecule inhibitors with high binding affinity. We have implemented a virtual screening workflow to identify potential candidate molecules. This process has resulted in the selection of ten molecules. Subsequently, these ten molecules have undergone biological activity evaluation to assess their potential efficacy. Impressively, molecule compound 6 surfaced as the most promising, exhibiting a potent kinase inhibitory activity marked by an IC50 of 130.1 nM and a notable reduction in TNF-α release within macrophages. This suggests that compound 6 could potentially serve as an effective inhibitor for the treatment of neuroinflammation and neurodegenerative diseases. The prospect of further medicinal modifications to optimize compound 6 presents a promising avenue for future research and development in this field. Utilizing binding pose metadynamics coupled with molecular dynamics simulations, we delved into the explicit binding mode of compound 6 to JNK3. Such insights pave the way for refined drug development strategies. Collectively, our results underscore the efficacy of the hybrid virtual screening workflow in the identification of robust JNK3 inhibitors, holding promise for innovative treatments against neuroinflammation and neurodegenerative disorders.