基于激酶的蛋白水解靶向嵌合体研究进展

Latest development of proteolysis-targeting chimera for kinases

蛋白激酶是当前药物化学研究中最受关注的目标之一,在各种疾病如癌症、炎症或自身免疫性疾病的病理生理过程中发挥了重要的作用,因此开发以蛋白激酶为靶点的药物受到了广泛关注。自20世纪80年代以来,尽管许多有效的激酶抑制剂被陆续开发上市,但激酶抑制剂常存在耐药性和非靶向性等亟待解决的问题。为此,研究者致力于将有效的激酶抑制剂开发成蛋白水解靶向嵌合体(Proteolysis-targeting chimera, PROTAC),通过选择性地降解目标蛋白激酶来克服小分子抑制剂的耐药性问题。本文重点讨论了应用于激酶的PROTAC技术的最新发现,特别关注了2018年以来发表的化合物。

Protein kinase higly sought-aftr targets in current medicinal medicinal chemistry research.It plays a crucial role in the pathophysiological processes of various diseases including cancer,inflammation and autoimmune diseases.Therefore,there is significant interest in developing drugs that target protein kinase.While many effective kinase inhibitors have been developed and approved since the 1980s,they often encounter challenges such as drug resistance and non-targeting effect.To address these limitations.researchers devote to converting effective kinase inhibitors into proteolysis-targeting chimera(PROTAC),which offers the potential to conquer the resistance of molecule inhibitors by degrading target kinase selectively.Recent advancements in PROTAC technology applied to kinases are highly discussed,with a particular focus on compounds published since 2018.