2-氨基-7-磺酰基- 7h -吡咯[2,3-d]嘧啶衍生物作为有效可逆FGFR抑制剂的发现,具有Gatekeeper突变耐受性:设计、合成和生物学评价

IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL
Wuchen Xie, Siyu Yang, Li Liang, Meng Wang, Wen Zuo, Yan Lei, Yanmin Zhang, Weifang Tang, Tao Lu*, Yadong Chen* and Yulei Jiang*, 
{"title":"2-氨基-7-磺酰基- 7h -吡咯[2,3-d]嘧啶衍生物作为有效可逆FGFR抑制剂的发现,具有Gatekeeper突变耐受性:设计、合成和生物学评价","authors":"Wuchen Xie,&nbsp;Siyu Yang,&nbsp;Li Liang,&nbsp;Meng Wang,&nbsp;Wen Zuo,&nbsp;Yan Lei,&nbsp;Yanmin Zhang,&nbsp;Weifang Tang,&nbsp;Tao Lu*,&nbsp;Yadong Chen* and Yulei Jiang*,&nbsp;","doi":"10.1021/acs.jmedchem.2c01420","DOIUrl":null,"url":null,"abstract":"<p >Fibroblast growth factor receptors (FGFRs) play key roles in promoting cancer cell proliferation, differentiation, and migration. However, acquired resistance to FGFR inhibitors has become an emerging challenge in long-term cancer therapies, especially for hepatocellular carcinoma (HCC). Gatekeeper (GK) mutations are the main mechanism of resistance. Herein, we describe the discovery of a series of reversible FGFR inhibitors, particularly for GK mutations with the 2-amino-7-sulfonyl-7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidine scaffold. Rational design, optimization, and pharmacokinetic screening provided representative compound <b>19</b> with potent FGFR inhibition in vitro, high bioavailability, and an acceptable half-life. GK mutation tolerance was supported by assays against FGFR4<sup>V550L</sup> and Ba/F3-TEL-FGFR4<sup>V550L</sup> cells. Moreover, compound <b>19</b> exhibited potent antitumor potency in HUH7 xenograft mouse models with no obvious toxicity observed. Compound <b>19</b> was identified as a potential candidate for overcoming GK mutations for HCC treatment.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"65 24","pages":"16570–16588"},"PeriodicalIF":6.8000,"publicationDate":"2022-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"2","resultStr":"{\"title\":\"Discovery of 2-Amino-7-sulfonyl-7H-pyrrolo[2,3-d]pyrimidine Derivatives as Potent Reversible FGFR Inhibitors with Gatekeeper Mutation Tolerance: Design, Synthesis, and Biological Evaluation\",\"authors\":\"Wuchen Xie,&nbsp;Siyu Yang,&nbsp;Li Liang,&nbsp;Meng Wang,&nbsp;Wen Zuo,&nbsp;Yan Lei,&nbsp;Yanmin Zhang,&nbsp;Weifang Tang,&nbsp;Tao Lu*,&nbsp;Yadong Chen* and Yulei Jiang*,&nbsp;\",\"doi\":\"10.1021/acs.jmedchem.2c01420\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Fibroblast growth factor receptors (FGFRs) play key roles in promoting cancer cell proliferation, differentiation, and migration. However, acquired resistance to FGFR inhibitors has become an emerging challenge in long-term cancer therapies, especially for hepatocellular carcinoma (HCC). Gatekeeper (GK) mutations are the main mechanism of resistance. Herein, we describe the discovery of a series of reversible FGFR inhibitors, particularly for GK mutations with the 2-amino-7-sulfonyl-7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidine scaffold. Rational design, optimization, and pharmacokinetic screening provided representative compound <b>19</b> with potent FGFR inhibition in vitro, high bioavailability, and an acceptable half-life. GK mutation tolerance was supported by assays against FGFR4<sup>V550L</sup> and Ba/F3-TEL-FGFR4<sup>V550L</sup> cells. Moreover, compound <b>19</b> exhibited potent antitumor potency in HUH7 xenograft mouse models with no obvious toxicity observed. Compound <b>19</b> was identified as a potential candidate for overcoming GK mutations for HCC treatment.</p>\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":\"65 24\",\"pages\":\"16570–16588\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2022-12-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"2\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01420\",\"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.2c01420","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 2

摘要

成纤维细胞生长因子受体(FGFRs)在促进癌细胞增殖、分化和迁移中起着关键作用。然而,对FGFR抑制剂的获得性耐药已成为长期癌症治疗的新挑战,特别是对于肝细胞癌(HCC)。Gatekeeper (GK)突变是耐药的主要机制。在本文中,我们描述了一系列可逆FGFR抑制剂的发现,特别是对于具有2-氨基-7-磺酰基- 7h -吡咯[2,3-d]嘧啶支架的GK突变。合理的设计、优化和药代动力学筛选提供了具有代表性的化合物19在体外具有有效的FGFR抑制作用、高生物利用度和可接受的半衰期。针对FGFR4V550L和Ba/F3-TEL-FGFR4V550L细胞的试验支持GK突变耐受性。此外,化合物19在HUH7异种移植小鼠模型中表现出较强的抗肿瘤能力,无明显毒性。化合物19被确定为克服GK突变治疗HCC的潜在候选者。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Discovery of 2-Amino-7-sulfonyl-7H-pyrrolo[2,3-d]pyrimidine Derivatives as Potent Reversible FGFR Inhibitors with Gatekeeper Mutation Tolerance: Design, Synthesis, and Biological Evaluation

Discovery of 2-Amino-7-sulfonyl-7H-pyrrolo[2,3-d]pyrimidine Derivatives as Potent Reversible FGFR Inhibitors with Gatekeeper Mutation Tolerance: Design, Synthesis, and Biological Evaluation

Fibroblast growth factor receptors (FGFRs) play key roles in promoting cancer cell proliferation, differentiation, and migration. However, acquired resistance to FGFR inhibitors has become an emerging challenge in long-term cancer therapies, especially for hepatocellular carcinoma (HCC). Gatekeeper (GK) mutations are the main mechanism of resistance. Herein, we describe the discovery of a series of reversible FGFR inhibitors, particularly for GK mutations with the 2-amino-7-sulfonyl-7H-pyrrolo[2,3-d]pyrimidine scaffold. Rational design, optimization, and pharmacokinetic screening provided representative compound 19 with potent FGFR inhibition in vitro, high bioavailability, and an acceptable half-life. GK mutation tolerance was supported by assays against FGFR4V550L and Ba/F3-TEL-FGFR4V550L cells. Moreover, compound 19 exhibited potent antitumor potency in HUH7 xenograft mouse models with no obvious toxicity observed. Compound 19 was identified as a potential candidate for overcoming GK mutations for HCC treatment.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Journal of Medicinal Chemistry
Journal of Medicinal Chemistry 医学-医药化学
CiteScore
4.00
自引率
11.00%
发文量
804
审稿时长
1.9 months
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.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信