Lei Ye , Zhenzhen Cui , Yu Sun , Haikun Zhou , Quanjin Rong , Dan Wang , Jiaming Jin , Qijian Zhang , Di Kang , Lihong Hu , Junwei Wang
{"title":"发现用于治疗急性髓性白血病的基于吉尔替尼的 FLT3-PROTAC 强效降解剂","authors":"Lei Ye , Zhenzhen Cui , Yu Sun , Haikun Zhou , Quanjin Rong , Dan Wang , Jiaming Jin , Qijian Zhang , Di Kang , Lihong Hu , Junwei Wang","doi":"10.1016/j.bioorg.2024.107477","DOIUrl":null,"url":null,"abstract":"<div><p>Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis targeting chimeras (PROTACs) emerge as a promising approach to overcome the limitations of FLT3 inhibitors, while the development of orally bioavailable FLT3-PROTACs faces great challenges. Here, we report the rational design and evaluation of a series of Gilteritinib-based FLT3-PROTACs. Among them, <strong>B3-2</strong> exhibited the strongest antiproliferative activity against FLT3-ITD mutant AML cells, and significantly induced FLT3-ITD protein degradation. Mechanistic investigations demonstrated that <strong>B3-2</strong> induced FLT3-ITD degradation in a ubiquitin–proteasome-dependent manner. More importantly, <strong>B3-2</strong> exhibited an oral bioavailability of 5.65%, and oral administration of <strong>B3-2</strong> showed good antitumor activity in MV-4-11 xenograft models. Furthermore, <strong>B3-2</strong> showed strong antiproliferative activity against FLT3 resistant mutations, highlighting its potential in overcoming drug resistance.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5000,"publicationDate":"2024-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of a potent Gilteritinib-based FLT3-PROTAC degrader for the treatment of Acute myeloid leukemia\",\"authors\":\"Lei Ye , Zhenzhen Cui , Yu Sun , Haikun Zhou , Quanjin Rong , Dan Wang , Jiaming Jin , Qijian Zhang , Di Kang , Lihong Hu , Junwei Wang\",\"doi\":\"10.1016/j.bioorg.2024.107477\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis targeting chimeras (PROTACs) emerge as a promising approach to overcome the limitations of FLT3 inhibitors, while the development of orally bioavailable FLT3-PROTACs faces great challenges. Here, we report the rational design and evaluation of a series of Gilteritinib-based FLT3-PROTACs. Among them, <strong>B3-2</strong> exhibited the strongest antiproliferative activity against FLT3-ITD mutant AML cells, and significantly induced FLT3-ITD protein degradation. Mechanistic investigations demonstrated that <strong>B3-2</strong> induced FLT3-ITD degradation in a ubiquitin–proteasome-dependent manner. More importantly, <strong>B3-2</strong> exhibited an oral bioavailability of 5.65%, and oral administration of <strong>B3-2</strong> showed good antitumor activity in MV-4-11 xenograft models. Furthermore, <strong>B3-2</strong> showed strong antiproliferative activity against FLT3 resistant mutations, highlighting its potential in overcoming drug resistance.</p></div>\",\"PeriodicalId\":257,\"journal\":{\"name\":\"Bioorganic Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2024-05-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic Chemistry\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0045206824003821\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic Chemistry","FirstCategoryId":"92","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0045206824003821","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Discovery of a potent Gilteritinib-based FLT3-PROTAC degrader for the treatment of Acute myeloid leukemia
Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis targeting chimeras (PROTACs) emerge as a promising approach to overcome the limitations of FLT3 inhibitors, while the development of orally bioavailable FLT3-PROTACs faces great challenges. Here, we report the rational design and evaluation of a series of Gilteritinib-based FLT3-PROTACs. Among them, B3-2 exhibited the strongest antiproliferative activity against FLT3-ITD mutant AML cells, and significantly induced FLT3-ITD protein degradation. Mechanistic investigations demonstrated that B3-2 induced FLT3-ITD degradation in a ubiquitin–proteasome-dependent manner. More importantly, B3-2 exhibited an oral bioavailability of 5.65%, and oral administration of B3-2 showed good antitumor activity in MV-4-11 xenograft models. Furthermore, B3-2 showed strong antiproliferative activity against FLT3 resistant mutations, highlighting its potential in overcoming drug resistance.
期刊介绍：
Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry.
For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature.
The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.
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