Bhujbal Swapnil P, Hah Jung-Mi
College of Pharmacy, Hanyang University, Ansan 426-791, Republic of Korea.
Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 426-791, Republic of Korea.
Pharmaceuticals (Basel). 2023 Sep 13;16(9):1295. doi: 10.3390/ph16091295.
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.
由于在癌症、自身免疫性疾病、心血管疾病、神经退行性疾病和炎症性疾病等各种疾病中蛋白激酶活性失调，蛋白激酶家族已成为21世纪关键的药物靶点。值得注意的是，许多激酶已被用作靶点，使用传统的ATP模拟激酶抑制剂来治疗癌症和神经退行性疾病。同样，不可逆共价抑制剂也已被开发用于不同类型的癌症。将共价修饰应用于靶向蛋白已在癌症治疗方面取得了重大进展。然而，虽然共价药物对医学治疗产生了重大影响，但其在神经退行性疾病中的潜力在很大程度上仍未得到探索。神经退行性疾病对脑功能构成重大风险，导致感觉、运动和认知能力逐渐恶化。阿尔茨海默病（AD）、亨廷顿舞蹈症（HD）、帕金森病（PD）和多发性硬化症（MS）就是这类疾病的各种例子。许多研究小组已经通过关于FDA批准的共价抑制剂的综述和研究文章报告了相关见解，详细揭示了它们的作用机制以及优先与特定氨基酸残基相互作用的特定共价弹头。因此，在本综述中，我们旨在对这些关键主题进行简要总结。这一总结旨在指导药物化学家设计针对蛋白激酶的共价抑制剂，特别是针对神经退行性疾病的抑制剂。
