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

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.