Tian-Hua Wei , Yun Zhou , Jin Yang , Meng-Yuan Zhang , Jing-Jing Wang , Zhen-Jiang Tong , Jia-Zhen Wu , Yi-Bo Wang , Jiu-Kai Sha , Min Chen , Ning Ding , Yan-Cheng Yu , Wei-Chen Dai , Xue-Jiao Leng , Xin Xue , Shan-Liang Sun , Xiao-Long Wang , Nian-Guang Li , Zhi-Hao Shi
{"title":"Design and synthesis 1H-Pyrrolo[2,3-b]pyridine derivatives as FLT3 inhibitors for the treatment of Acute myeloid Leukemia","authors":"Tian-Hua Wei , Yun Zhou , Jin Yang , Meng-Yuan Zhang , Jing-Jing Wang , Zhen-Jiang Tong , Jia-Zhen Wu , Yi-Bo Wang , Jiu-Kai Sha , Min Chen , Ning Ding , Yan-Cheng Yu , Wei-Chen Dai , Xue-Jiao Leng , Xin Xue , Shan-Liang Sun , Xiao-Long Wang , Nian-Guang Li , Zhi-Hao Shi","doi":"10.1016/j.bmc.2024.117631","DOIUrl":null,"url":null,"abstract":"<div><p>Acute myeloid leukemia (AML) is the most common type of blood cancer and has been strongly correlated with the overexpression of Fms-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family. With the emergence of FLT3 internal tandem duplication alteration (ITD) and tyrosine kinase domain (TKD) mutations, the development of FLT3 small molecule inhibitors has become an effective medicinal chemistry strategy for AML. Herein, we have designed and synthesized two series of 1<em>H</em>-pyrrolo[2,3-<em>b</em>]pyridine derivatives <strong>CM1</strong>–<strong>CM24</strong>, as FLT3 inhibitors based on <strong>F14</strong>, which we previously reported, that can target the hydrophobic FLT3 back pocket. Among these derivates, <strong>CM5</strong> showed significant inhibition of FLT3 and FLT3-ITD, with inhibitory percentages of 57.72 % and 53.77 % respectively at the concentration of 1 μΜ. Furthermore, <strong>CM5</strong> demonstrated potent inhibition against FLT3-dependent human AML cell lines MOLM-13 and MV4-11 (both harboring FLT3<strong>-</strong>ITD mutant), with IC<sub>50</sub> values of 0.75 μM and 0.64 μM respectively. In our cellular mechanistic studies, <strong>CM5</strong> also effectively induces apoptosis by arresting cell cycle progression in the G0/G1 phase. In addition, the amide and urea linker function were discussed in detail based on computational simulations studies. <strong>CM5</strong> will serve as a novel lead compound for further structural modification and development of FLT3 inhibitors specifically targeting AML with FLT3<strong>-</strong>ITD mutations.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0968089624000452","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Acute myeloid leukemia (AML) is the most common type of blood cancer and has been strongly correlated with the overexpression of Fms-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family. With the emergence of FLT3 internal tandem duplication alteration (ITD) and tyrosine kinase domain (TKD) mutations, the development of FLT3 small molecule inhibitors has become an effective medicinal chemistry strategy for AML. Herein, we have designed and synthesized two series of 1H-pyrrolo[2,3-b]pyridine derivatives CM1–CM24, as FLT3 inhibitors based on F14, which we previously reported, that can target the hydrophobic FLT3 back pocket. Among these derivates, CM5 showed significant inhibition of FLT3 and FLT3-ITD, with inhibitory percentages of 57.72 % and 53.77 % respectively at the concentration of 1 μΜ. Furthermore, CM5 demonstrated potent inhibition against FLT3-dependent human AML cell lines MOLM-13 and MV4-11 (both harboring FLT3-ITD mutant), with IC50 values of 0.75 μM and 0.64 μM respectively. In our cellular mechanistic studies, CM5 also effectively induces apoptosis by arresting cell cycle progression in the G0/G1 phase. In addition, the amide and urea linker function were discussed in detail based on computational simulations studies. CM5 will serve as a novel lead compound for further structural modification and development of FLT3 inhibitors specifically targeting AML with FLT3-ITD mutations.
期刊介绍:
Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides.
The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.