Junwei Wang*, Xiang Pan, Yi Song, Jian Liu, Fei Ma, Ping Wang, Yan Liu, Lin Zhao, Di Kang*, Lihong Hu*
{"title":"一种有效的选择性FLT3抑制剂(Z)- n-(5-((5-氟-2-氧吲哚-3-酰基)甲基)-4-甲基- 1h -吡咯烷-3-基)-3-(吡咯烷-1-基)丙酰胺的发现,对FLT3- itd阳性急性髓系白血病具有改善的药物样特性和优越的疗效","authors":"Junwei Wang*, Xiang Pan, Yi Song, Jian Liu, Fei Ma, Ping Wang, Yan Liu, Lin Zhao, Di Kang*, Lihong Hu*","doi":"10.1021/acs.jmedchem.0c02247","DOIUrl":null,"url":null,"abstract":"<p >Overcoming the FLT3-ITD mutant has been a promising drug design strategy for treating acute myeloid leukemia (AML). Herein, we discovered a novel FLT3 inhibitor <b>17</b>, which displayed potent inhibitory activity against the FLT3-ITD mutant (IC<sub>50</sub> = 0.8 nM) and achieved good selectivity over c-KIT kinase (over 500-fold). Compound <b>17</b> selectively inhibited the proliferation of FLT3-ITD-positive AML cell lines MV4-11 (IC<sub>50</sub> = 23.5 nM) and MOLM-13 (IC<sub>50</sub> = 35.5 nM) and exhibited potent inhibitory effects against associated acquired resistance mutations. In cellular mechanism studies, compound <b>17</b> strongly inhibited FLT3-mediated signaling pathways and induced apoptosis by arresting the cell cycle in the sub-G1 phase. In in vivo studies, compound <b>17</b> demonstrated a good bioavailability (73.6%) and significantly suppressed tumor growth in MV4-11 (10 mg/kg, TGI 93.4%) and MOLM-13 (20 mg/kg, TGI 98.0%) xenograft models without exhibiting obvious toxicity. These results suggested that compound <b>17</b> may be a promising drug candidate for treating FLT3-ITD-positive AML.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2021-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acs.jmedchem.0c02247","citationCount":"11","resultStr":"{\"title\":\"Discovery of a Potent and Selective FLT3 Inhibitor (Z)-N-(5-((5-Fluoro-2-oxoindolin-3-ylidene)methyl)-4-methyl-1H-pyrrol-3-yl)-3-(pyrrolidin-1-yl)propanamide with Improved Drug-like Properties and Superior Efficacy in FLT3-ITD-Positive Acute Myeloid Leukemia\",\"authors\":\"Junwei Wang*, Xiang Pan, Yi Song, Jian Liu, Fei Ma, Ping Wang, Yan Liu, Lin Zhao, Di Kang*, Lihong Hu*\",\"doi\":\"10.1021/acs.jmedchem.0c02247\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Overcoming the FLT3-ITD mutant has been a promising drug design strategy for treating acute myeloid leukemia (AML). Herein, we discovered a novel FLT3 inhibitor <b>17</b>, which displayed potent inhibitory activity against the FLT3-ITD mutant (IC<sub>50</sub> = 0.8 nM) and achieved good selectivity over c-KIT kinase (over 500-fold). Compound <b>17</b> selectively inhibited the proliferation of FLT3-ITD-positive AML cell lines MV4-11 (IC<sub>50</sub> = 23.5 nM) and MOLM-13 (IC<sub>50</sub> = 35.5 nM) and exhibited potent inhibitory effects against associated acquired resistance mutations. In cellular mechanism studies, compound <b>17</b> strongly inhibited FLT3-mediated signaling pathways and induced apoptosis by arresting the cell cycle in the sub-G1 phase. In in vivo studies, compound <b>17</b> demonstrated a good bioavailability (73.6%) and significantly suppressed tumor growth in MV4-11 (10 mg/kg, TGI 93.4%) and MOLM-13 (20 mg/kg, TGI 98.0%) xenograft models without exhibiting obvious toxicity. These results suggested that compound <b>17</b> may be a promising drug candidate for treating FLT3-ITD-positive AML.</p>\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2021-04-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1021/acs.jmedchem.0c02247\",\"citationCount\":\"11\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c02247\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c02247","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Discovery of a Potent and Selective FLT3 Inhibitor (Z)-N-(5-((5-Fluoro-2-oxoindolin-3-ylidene)methyl)-4-methyl-1H-pyrrol-3-yl)-3-(pyrrolidin-1-yl)propanamide with Improved Drug-like Properties and Superior Efficacy in FLT3-ITD-Positive Acute Myeloid Leukemia
Overcoming the FLT3-ITD mutant has been a promising drug design strategy for treating acute myeloid leukemia (AML). Herein, we discovered a novel FLT3 inhibitor 17, which displayed potent inhibitory activity against the FLT3-ITD mutant (IC50 = 0.8 nM) and achieved good selectivity over c-KIT kinase (over 500-fold). Compound 17 selectively inhibited the proliferation of FLT3-ITD-positive AML cell lines MV4-11 (IC50 = 23.5 nM) and MOLM-13 (IC50 = 35.5 nM) and exhibited potent inhibitory effects against associated acquired resistance mutations. In cellular mechanism studies, compound 17 strongly inhibited FLT3-mediated signaling pathways and induced apoptosis by arresting the cell cycle in the sub-G1 phase. In in vivo studies, compound 17 demonstrated a good bioavailability (73.6%) and significantly suppressed tumor growth in MV4-11 (10 mg/kg, TGI 93.4%) and MOLM-13 (20 mg/kg, TGI 98.0%) xenograft models without exhibiting obvious toxicity. These results suggested that compound 17 may be a promising drug candidate for treating FLT3-ITD-positive AML.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.