靶向PD-L1相关抑制剂以及降解剂的研究进展
Research progress in targeted PD-L1 related inhibitors and degraders
肖瑶 1祝亚文1
作者信息
- 1. 武汉科技大学附属武昌医院药学部,武汉 430063
- 折叠
摘要
肿瘤免疫疗法正在彻底改变癌症的治疗方式,其提高了多种癌症患者的总生存期和无进展生存期.免疫检查点抑制剂通过阻断程序性死亡受体1(PD-1)和程序性死亡受体配体1(PD-L1)的相互结合,重新激活细胞毒性T细胞(CTL)的抗癌活性,发挥免疫抗肿瘤作用.然而,PD-1/PD-L1单抗临床有效率为10％～30％,同时会产生严重的治疗相关不良反应,如免疫性心肌炎.小分子化合物在药动学方面具有诸多优势,如口服生物利用度好、对相关组织和肿瘤细胞渗透率高、半衰期合理等.目前,小分子肿瘤免疫药物的研发已成为癌症免疫治疗领域的热门方向.本文将总结近5年肿瘤免疫治疗小分子调节剂的最新进展,包括PD-L1小分子抑制剂、基于蛋白水解靶向嵌合体和溶酶体靶向嵌合体技术的PD-L1降解剂,并讨论PD-L1小分子调节剂的未来发展方向,为肿瘤免疫治疗提供新的理论参考.
Abstract
Tumor immunotherapy is revolutionizing the treatment approach for cancer,and has significantly improved overall survival and progression-free survival in various types of cancer patients.The mechanism of action for immune checkpoint inhibitors involves blocking the interaction between programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1),thereby reactivating the anti-cancer activity of cytotoxic T cells and exerting an immune-mediated anti-cancer effect.However,the PD-1/PD-L1 monoclonal antibody has a clinical efficacy rate of only about 10％-30％,and can also cause severe treatment-related adverse reactions such as immune myocarditis.Small molecule compounds have several advantages in terms of pharmacokinetics,such as better oral bioavailability,higher penetration into relevant tissues and tumor cells,and reasonable half-life.Currently,the development of small-molecule tumor immunotherapeutic drugs has become a highly active research field in cancer immunotherapy.This article aims to summarize the recent advancements in small molecule research for tumor immunotherapy over the past five years,including PD-L1 small molecule inhibitors,PD-L1 degraders based on proteolysis-targeting chimeras,and lysosome-targeting chimeras technologies,and discuss the future directions for the development of small molecule inhibitors,providing new theoretical references for tumor immunotherapy.
关键词
免疫治疗/降解剂/小分子抑制剂/程序性死亡受体1/程序性死亡受体配体1/蛋白水解靶向嵌合体/溶酶体靶向嵌合体Key words
Immunotherapy/Degraders/Small molecule inhibitors/Programmed death-1/programmed ligand death-1/Proteolysis-targeting chimeras/Lysosome-targeting chimeras technologies引用本文复制引用
出版年
2024
NETL
NSTL
万方数据