{"title":"针对非小细胞肺癌的 RET 小分子抑制剂的最新研究进展","authors":"Jiayi Shen, Liping Chen, Yulan Song, Sheng Chen, Wei Guo, Yongdong Li","doi":"10.1186/s41120-024-00094-z","DOIUrl":null,"url":null,"abstract":"Since the oncogenic rearranged during transfection (RET) gene fusion was discovered in non-small cell lung cancer (NSCLC) in 2012, multiple-targeted kinase inhibitors (MKIs) cabozantinib and vandetanib have been explored in the clinic for RET positive NSCLC patients. As the nonselective nature of these inhibitors, patients have off-target adverse effects. The discovery of highly potent selective RET inhibitors such as pralsetinib and selpercatinib improve the clinic efficiency and more favorable toxicity profile. However, acquired resistance mediated by secondary mutations in the solvent-front region of the kinase (e.g. G810C/S/R) become a new challenge for selective RET inhibitor therapies. In this review, we highlight typical RET inhibitors developed during these years and provide a reference for more potential RET inhibitors exploration in the future.","PeriodicalId":453,"journal":{"name":"AAPS Open","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Recent progress of small-molecule of RET inhibitors against Non-small cell lung cancer\",\"authors\":\"Jiayi Shen, Liping Chen, Yulan Song, Sheng Chen, Wei Guo, Yongdong Li\",\"doi\":\"10.1186/s41120-024-00094-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Since the oncogenic rearranged during transfection (RET) gene fusion was discovered in non-small cell lung cancer (NSCLC) in 2012, multiple-targeted kinase inhibitors (MKIs) cabozantinib and vandetanib have been explored in the clinic for RET positive NSCLC patients. As the nonselective nature of these inhibitors, patients have off-target adverse effects. The discovery of highly potent selective RET inhibitors such as pralsetinib and selpercatinib improve the clinic efficiency and more favorable toxicity profile. However, acquired resistance mediated by secondary mutations in the solvent-front region of the kinase (e.g. G810C/S/R) become a new challenge for selective RET inhibitor therapies. In this review, we highlight typical RET inhibitors developed during these years and provide a reference for more potential RET inhibitors exploration in the future.\",\"PeriodicalId\":453,\"journal\":{\"name\":\"AAPS Open\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-06-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"AAPS Open\",\"FirstCategoryId\":\"1\",\"ListUrlMain\":\"https://doi.org/10.1186/s41120-024-00094-z\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"AAPS Open","FirstCategoryId":"1","ListUrlMain":"https://doi.org/10.1186/s41120-024-00094-z","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
摘要
自2012年在非小细胞肺癌(NSCLC)中发现致癌重排转染(RET)基因融合以来,多靶点激酶抑制剂(MKIs)卡博赞替尼(cabozantinib)和万替尼(vandetanib)已在临床上用于治疗RET阳性NSCLC患者。由于这些抑制剂的非选择性,患者会出现脱靶不良反应。普拉塞替尼和色瑞帕替尼等强效选择性 RET 抑制剂的发现提高了临床效率,并改善了毒性状况。然而,由激酶溶剂前区二次突变(如 G810C/S/R)介导的获得性耐药性成为选择性 RET 抑制剂疗法面临的新挑战。在这篇综述中,我们将重点介绍这几年开发的典型 RET 抑制剂,并为未来探索更多潜在的 RET 抑制剂提供参考。
Recent progress of small-molecule of RET inhibitors against Non-small cell lung cancer
Since the oncogenic rearranged during transfection (RET) gene fusion was discovered in non-small cell lung cancer (NSCLC) in 2012, multiple-targeted kinase inhibitors (MKIs) cabozantinib and vandetanib have been explored in the clinic for RET positive NSCLC patients. As the nonselective nature of these inhibitors, patients have off-target adverse effects. The discovery of highly potent selective RET inhibitors such as pralsetinib and selpercatinib improve the clinic efficiency and more favorable toxicity profile. However, acquired resistance mediated by secondary mutations in the solvent-front region of the kinase (e.g. G810C/S/R) become a new challenge for selective RET inhibitor therapies. In this review, we highlight typical RET inhibitors developed during these years and provide a reference for more potential RET inhibitors exploration in the future.