CAJ | 학술논문

酪氨酸激酶的过度表达和过度激活在许多肿瘤的发生和发展中具有重要意义，因此，多种酪氨酸激酶成为抗肿瘤药物的靶点。目前已经上市的小分子酪氨酸激酶抑制剂多属于可逆性抑制剂，这些药物具有选择性差、药效不够强烈和持久以及易引发耐药性等缺点。近些年，不可逆性酪氨酸激酶抑制剂的研究正方兴未艾。这一类药物分子以不可逆的共价键与酪氨酸激酶上ATP结合域进行结合，从而使该靶点永久性失活。由于其独特的作用机制，不可逆性酪氨酸激酶抑制剂可以有效地解决可逆性酪氨酸激酶抑制剂的几个缺点。目前，已经有一批不可逆性酪氨酸激酶抑制剂进入市场或临床研究阶段。该篇综述是对不可逆性酪氨酸激酶抑制剂的结构、药理和药化特征及其研究进展等进行总结和阐述。
락안산격매적과도표체화과도격활재허다종류적발생화발전중구유중요의의，인차，다충락안산격매성위항종류약물적파점。목전이경상시적소분자락안산격매억제제다속우가역성억제제，저사약물구유선택성차、약효불구강렬화지구이급역인발내약성등결점。근사년，불가역성락안산격매억제제적연구정방흥미애。저일류약물분자이불가역적공개건여락안산격매상ATP결합역진행결합，종이사해파점영구성실활。유우기독특적작용궤제，불가역성락안산격매억제제가이유효지해결가역성락안산격매억제제적궤개결점。목전，이경유일비불가역성락안산격매억제제진입시장혹림상연구계단。해편종술시대불가역성락안산격매억제제적결구、약리화약화특정급기연구진전등진행총결화천술。
Dysfunction in tyrosine kinase activity disrupts the nor-mal control of cellular phosphorylation signaling pathways,which plays a vital role in genesis and development of various tumors, and makes tyrosine kinases a class of targets of many anti-tumor drugs. Currently most approved tyrosine kinase inhibitors ( TKIs) are based on irreversible binding mechanisms, making them poorly selective, not potent or sustained enough regarding pharmacological effects and prone to triggering resistance. In the past decade, much progress has been made in the development of <br> a new class of TKIs which irreversibly inhibit their target proteins via the formation of covalent bonds, overcoming the drawbacks of irreversible TKIs. Several irreversible TKIs have entered markets or clinical research phases. This review is to summarize the structural, pharmacological and medicinal chemical properties of investigational and marketed irreversible TKIs as well as their re-cent developments.