College of Pharmacy, CHA University, Pocheon-si, Gyeonggi-do, 11160, Republic of Korea.
College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
Eur J Med Chem. 2021 Apr 15;216:113318. doi: 10.1016/j.ejmech.2021.113318. Epub 2021 Feb 23.
Identifying a pharmacological agent that targets only one of more than 500 kinases present in humans is an important challenge. One potential solution to this problem is the development of bivalent kinase inhibitors, which consist of two connected fragments, each bind to a dissimilar binding site of the bisubstrate enzyme. The main advantage of bivalent (type V) kinase inhibitors is generating more interactions with target enzymes that can enhance the molecules' selectivity and affinity compared to single-site inhibitors. Earlier type V inhibitors were not suitable for the cellular environment and were mostly used in in vitro studies. However, recently developed bivalent compounds have high kinase affinity, high biological and chemical stability in vivo. This review summarized the hetero-bivalent kinase inhibitors described in the literature from 2014 to the present. We attempted to classify the molecules by serine/threonine and tyrosine kinase inhibitors, and then each target kinase and its hetero-bivalent inhibitor was assessed in depth. In addition, we discussed the analysis of advantages, limitations, and perspectives of bivalent kinase inhibitors compared with the monovalent kinase inhibitors.
鉴定仅针对人类中存在的 500 多种激酶之一的药理学药物是一个重要的挑战。解决此问题的一种潜在方法是开发双价激酶抑制剂，其由两个连接的片段组成，每个片段与双底物酶的不同结合位点结合。双价（V 型）激酶抑制剂的主要优点是与靶酶形成更多相互作用，与单一位点抑制剂相比，可提高分子的选择性和亲和力。早期的 V 型抑制剂不适合细胞环境，主要用于体外研究。然而，最近开发的双价化合物具有高激酶亲和力，在体内具有高生物和化学稳定性。本综述总结了 2014 年至今文献中描述的杂双价激酶抑制剂。我们试图通过丝氨酸/苏氨酸和酪氨酸激酶抑制剂对分子进行分类，然后深入评估每个靶激酶及其杂双价抑制剂。此外，我们讨论了与单价激酶抑制剂相比，双价激酶抑制剂的优势、局限性和前景分析。
