{"title":"含环多胺的新型表皮生长因子受体酪氨酸激酶抑制剂的设计与活性评估","authors":"","doi":"10.1016/j.bmcl.2024.129961","DOIUrl":null,"url":null,"abstract":"<div><p>The EGFR-TK pathway is pivotal in non-small-cell lung cancer (NSCLC) treatment, drugs targeting both EGFR wild-type and mutant tumor cells are still urgently needed. The focus of our study is on ATP-competitive inhibitors crucial for NSCLC therapy, specifically targeting the epidermal growth factor receptor (EGFR). A series of derivatives of Erlotinib and Icotinib were developed by incorporating a macrocyclic polyamine into a quinazoline scaffold to enhance their inhibitory activity against drug-resistant cells. The compounds exhibit modest activity against EGFR triple mutants (EGFR<sup>del</sup><sup>19</sup><sup>/T790M/C797S</sup>). Compound b demonstrated slightly improved inhibition activity against PC-9<sup>d</sup><sup>el19/T790M/C797S</sup> (IC<sub>50</sub> = 496.3 nM). This could provide some insights for optimizing EGFR inhibitors, particularly in the context of EGFR triple mutants.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5000,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Design and activity evaluation of new EGFR tyrosine kinase inhibitors containing cyclic polyamines\",\"authors\":\"\",\"doi\":\"10.1016/j.bmcl.2024.129961\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>The EGFR-TK pathway is pivotal in non-small-cell lung cancer (NSCLC) treatment, drugs targeting both EGFR wild-type and mutant tumor cells are still urgently needed. The focus of our study is on ATP-competitive inhibitors crucial for NSCLC therapy, specifically targeting the epidermal growth factor receptor (EGFR). A series of derivatives of Erlotinib and Icotinib were developed by incorporating a macrocyclic polyamine into a quinazoline scaffold to enhance their inhibitory activity against drug-resistant cells. The compounds exhibit modest activity against EGFR triple mutants (EGFR<sup>del</sup><sup>19</sup><sup>/T790M/C797S</sup>). Compound b demonstrated slightly improved inhibition activity against PC-9<sup>d</sup><sup>el19/T790M/C797S</sup> (IC<sub>50</sub> = 496.3 nM). This could provide some insights for optimizing EGFR inhibitors, particularly in the context of EGFR triple mutants.</p></div>\",\"PeriodicalId\":256,\"journal\":{\"name\":\"Bioorganic & Medicinal Chemistry Letters\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.5000,\"publicationDate\":\"2024-09-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic & Medicinal Chemistry Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0960894X24003639\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0960894X24003639","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
摘要
表皮生长因子受体-TK通路是治疗非小细胞肺癌（NSCLC）的关键，目前仍急需同时针对表皮生长因子受体野生型和突变型肿瘤细胞的药物。我们的研究重点是对 NSCLC 治疗至关重要的 ATP 竞争性抑制剂，特别是针对表皮生长因子受体（EGFR）的抑制剂。通过在喹唑啉支架中加入大环多胺，我们开发了一系列厄洛替尼和艾柯替尼的衍生物，以增强它们对耐药细胞的抑制活性。这两种化合物对表皮生长因子受体三突变体（EGFRdel19/T790M/C797S）表现出适度的活性。化合物 b 对 PC-9del19/T790M/C797S 的抑制活性略有提高（IC50 = 496.3 nM）。这为优化表皮生长因子受体抑制剂，尤其是表皮生长因子受体三突变体抑制剂提供了一些启示。
Design and activity evaluation of new EGFR tyrosine kinase inhibitors containing cyclic polyamines
The EGFR-TK pathway is pivotal in non-small-cell lung cancer (NSCLC) treatment, drugs targeting both EGFR wild-type and mutant tumor cells are still urgently needed. The focus of our study is on ATP-competitive inhibitors crucial for NSCLC therapy, specifically targeting the epidermal growth factor receptor (EGFR). A series of derivatives of Erlotinib and Icotinib were developed by incorporating a macrocyclic polyamine into a quinazoline scaffold to enhance their inhibitory activity against drug-resistant cells. The compounds exhibit modest activity against EGFR triple mutants (EGFRdel19/T790M/C797S). Compound b demonstrated slightly improved inhibition activity against PC-9del19/T790M/C797S (IC50 = 496.3 nM). This could provide some insights for optimizing EGFR inhibitors, particularly in the context of EGFR triple mutants.
期刊介绍：
Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
