Jin Yang, Yan Zhang, Yue-Chu Li, Qing-Xin Wang, Meng-Yuan Zhang, Yu-Jing Xu, Jing-Jing Wang, Xiao-Ting Liang, Xiao-Long Jing, Shuang-Shuang Zhou, Qing-Qing Li, Zi-Xuan Wang, Yun Zhou, Nuo Qiao, Tian-Hua Wei, Ning Ding, Xin Xue, Yan-Cheng Yu, Xiao-Long Wang, Shan-Liang Sun, Wei-Chen Dai, Nian-Guang Li, Zhi-Hao Shi
{"title":"用于治疗急性髓性白血病的 I 型 FLT3 抑制剂的设计、合成和生物活性评估","authors":"Jin Yang, Yan Zhang, Yue-Chu Li, Qing-Xin Wang, Meng-Yuan Zhang, Yu-Jing Xu, Jing-Jing Wang, Xiao-Ting Liang, Xiao-Long Jing, Shuang-Shuang Zhou, Qing-Qing Li, Zi-Xuan Wang, Yun Zhou, Nuo Qiao, Tian-Hua Wei, Ning Ding, Xin Xue, Yan-Cheng Yu, Xiao-Long Wang, Shan-Liang Sun, Wei-Chen Dai, Nian-Guang Li, Zhi-Hao Shi","doi":"10.1002/ddr.70022","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>The abnormal overexpression of FLT3 kinase is intimately associated with pathogenesis of acute myeloid leukemia (AML), positioning FLT3 inhibitors as pivotal therapeutic agents. Despite the availability of three FDA-approved FLT3 inhibitors, their clinical utility is hampered by resistance stemming from tyrosine kinase domain (TKD) mutations. Through an integrative analysis of case studies, we identified a potential advantage of type I FLT3 inhibitors in overcoming TKD mutation-induced resistance. Structure–activity relationships (SAR) analysis indicated that <b>FW-1</b> exhibited over 50% inhibition against FLT3 at a concentration of 1 μM and demonstrated potent activity against AML cell lines MV4-11 (IC<sub>50</sub> = 2.68 μM) and MOLM-13 (IC<sub>50</sub> = 1.03 μM). In our cellular mechanistic studies, <b>FW-1</b> also effectively induced apoptosis by arresting cell cycle progression in the G0/G1 phase. This study introduces <b>FW-1</b> as a promising lead for type I FLT3 inhibitor, warranting further optimization.</p>\n </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 8","pages":""},"PeriodicalIF":3.5000,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Design, Synthesis, and Biological Activities Evaluation of Type I FLT3 Inhibitors for the Treatment of Acute Myeloid Leukemia\",\"authors\":\"Jin Yang, Yan Zhang, Yue-Chu Li, Qing-Xin Wang, Meng-Yuan Zhang, Yu-Jing Xu, Jing-Jing Wang, Xiao-Ting Liang, Xiao-Long Jing, Shuang-Shuang Zhou, Qing-Qing Li, Zi-Xuan Wang, Yun Zhou, Nuo Qiao, Tian-Hua Wei, Ning Ding, Xin Xue, Yan-Cheng Yu, Xiao-Long Wang, Shan-Liang Sun, Wei-Chen Dai, Nian-Guang Li, Zhi-Hao Shi\",\"doi\":\"10.1002/ddr.70022\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <p>The abnormal overexpression of FLT3 kinase is intimately associated with pathogenesis of acute myeloid leukemia (AML), positioning FLT3 inhibitors as pivotal therapeutic agents. Despite the availability of three FDA-approved FLT3 inhibitors, their clinical utility is hampered by resistance stemming from tyrosine kinase domain (TKD) mutations. Through an integrative analysis of case studies, we identified a potential advantage of type I FLT3 inhibitors in overcoming TKD mutation-induced resistance. Structure–activity relationships (SAR) analysis indicated that <b>FW-1</b> exhibited over 50% inhibition against FLT3 at a concentration of 1 μM and demonstrated potent activity against AML cell lines MV4-11 (IC<sub>50</sub> = 2.68 μM) and MOLM-13 (IC<sub>50</sub> = 1.03 μM). In our cellular mechanistic studies, <b>FW-1</b> also effectively induced apoptosis by arresting cell cycle progression in the G0/G1 phase. This study introduces <b>FW-1</b> as a promising lead for type I FLT3 inhibitor, warranting further optimization.</p>\\n </div>\",\"PeriodicalId\":11291,\"journal\":{\"name\":\"Drug Development Research\",\"volume\":\"85 8\",\"pages\":\"\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2024-11-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Drug Development Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/ddr.70022\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Development Research","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ddr.70022","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Design, Synthesis, and Biological Activities Evaluation of Type I FLT3 Inhibitors for the Treatment of Acute Myeloid Leukemia
The abnormal overexpression of FLT3 kinase is intimately associated with pathogenesis of acute myeloid leukemia (AML), positioning FLT3 inhibitors as pivotal therapeutic agents. Despite the availability of three FDA-approved FLT3 inhibitors, their clinical utility is hampered by resistance stemming from tyrosine kinase domain (TKD) mutations. Through an integrative analysis of case studies, we identified a potential advantage of type I FLT3 inhibitors in overcoming TKD mutation-induced resistance. Structure–activity relationships (SAR) analysis indicated that FW-1 exhibited over 50% inhibition against FLT3 at a concentration of 1 μM and demonstrated potent activity against AML cell lines MV4-11 (IC50 = 2.68 μM) and MOLM-13 (IC50 = 1.03 μM). In our cellular mechanistic studies, FW-1 also effectively induced apoptosis by arresting cell cycle progression in the G0/G1 phase. This study introduces FW-1 as a promising lead for type I FLT3 inhibitor, warranting further optimization.
期刊介绍：
Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.
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