p53激活剂和原黄酮的杂化分子靶向多发性骨髓瘤。

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-09-14 DOI:10.1002/cmdc.202500600
Francisca Lopes, Gábor Girst, Rafael Rincón, Ricardo J F Ferreira, Lídia M Gonçalves, Lucília Saraiva, Hui-Chun Wang, Muriel Cuendet, Attila Hunyadi, Maria M M Santos
{"title":"p53激活剂和原黄酮的杂化分子靶向多发性骨髓瘤。","authors":"Francisca Lopes, Gábor Girst, Rafael Rincón, Ricardo J F Ferreira, Lídia M Gonçalves, Lucília Saraiva, Hui-Chun Wang, Muriel Cuendet, Attila Hunyadi, Maria M M Santos","doi":"10.1002/cmdc.202500600","DOIUrl":null,"url":null,"abstract":"<p><p>Multiple myeloma is a rare blood cancer that develops from abnormal plasma cells in the bone marrow. Treatment of multiple myeloma remains an enormous challenge. In this work, hybrid compounds are developed and studied for their potential use against multiple myeloma. The compounds are designed to act by a dual mechanism of action, activation of the p53 pathway, and inhibition of the ataxia telangiectasia and Rad3-related protein (ATR). To evaluate the selectivity for the p53 pathway, the compounds are first evaluated in an isogenic pair of HCT116 colon cancer cell lines, with and without p53, and in two breast cancer cell lines expressing different forms of p53. Then, the growth inhibitory effect of the hybrid compounds is tested against the multiple myeloma cell lines RPMI 8226 (mutant p53) and MM.1S (wild-type p53). At the same time, compound 15 is confirmed to inhibit doxorubicin- but not UV-induced DNA damage response via the ATR/Chk1 signaling pathway. The hybrids show lower IC<sub>50</sub> values compared to the fragments alone, highlighting the potential for using hybrid molecules containing two pharmacophores with complementary activities. These results suggest that novel hybrid molecules may serve as new leads against multiple myeloma.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500600"},"PeriodicalIF":3.4000,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Hybrid Molecules of p53 Activators and Protoflavones to Target Multiple Myeloma.\",\"authors\":\"Francisca Lopes, Gábor Girst, Rafael Rincón, Ricardo J F Ferreira, Lídia M Gonçalves, Lucília Saraiva, Hui-Chun Wang, Muriel Cuendet, Attila Hunyadi, Maria M M Santos\",\"doi\":\"10.1002/cmdc.202500600\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Multiple myeloma is a rare blood cancer that develops from abnormal plasma cells in the bone marrow. Treatment of multiple myeloma remains an enormous challenge. In this work, hybrid compounds are developed and studied for their potential use against multiple myeloma. The compounds are designed to act by a dual mechanism of action, activation of the p53 pathway, and inhibition of the ataxia telangiectasia and Rad3-related protein (ATR). To evaluate the selectivity for the p53 pathway, the compounds are first evaluated in an isogenic pair of HCT116 colon cancer cell lines, with and without p53, and in two breast cancer cell lines expressing different forms of p53. Then, the growth inhibitory effect of the hybrid compounds is tested against the multiple myeloma cell lines RPMI 8226 (mutant p53) and MM.1S (wild-type p53). At the same time, compound 15 is confirmed to inhibit doxorubicin- but not UV-induced DNA damage response via the ATR/Chk1 signaling pathway. The hybrids show lower IC<sub>50</sub> values compared to the fragments alone, highlighting the potential for using hybrid molecules containing two pharmacophores with complementary activities. These results suggest that novel hybrid molecules may serve as new leads against multiple myeloma.</p>\",\"PeriodicalId\":147,\"journal\":{\"name\":\"ChemMedChem\",\"volume\":\" \",\"pages\":\"e202500600\"},\"PeriodicalIF\":3.4000,\"publicationDate\":\"2025-09-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ChemMedChem\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/cmdc.202500600\",\"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":"ChemMedChem","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/cmdc.202500600","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0

摘要

多发性骨髓瘤是一种罕见的血癌,由骨髓中的异常浆细胞发展而来。多发性骨髓瘤的治疗仍然是一个巨大的挑战。在这项工作中,开发和研究了混合化合物对多发性骨髓瘤的潜在应用。这些化合物具有双重作用机制,激活p53通路,抑制共济失调毛细血管扩张和rad3相关蛋白(ATR)。为了评估p53通路的选择性,我们首先在具有和不具有p53的HCT116结肠癌细胞系和表达不同形式p53的两种乳腺癌细胞系中对这些化合物进行了等基因评估。然后,测试了杂交化合物对多发性骨髓瘤细胞系RPMI 8226(突变型p53)和MM.1S(野生型p53)的生长抑制作用。同时,化合物15被证实通过ATR/Chk1信号通路抑制阿霉素诱导的DNA损伤反应,但不抑制紫外线诱导的DNA损伤反应。与单独的片段相比,杂交体的IC50值较低,突出了使用含有两个具有互补活性的药效团的杂交分子的潜力。这些结果表明,新的杂交分子可能成为治疗多发性骨髓瘤的新线索。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Hybrid Molecules of p53 Activators and Protoflavones to Target Multiple Myeloma.

Multiple myeloma is a rare blood cancer that develops from abnormal plasma cells in the bone marrow. Treatment of multiple myeloma remains an enormous challenge. In this work, hybrid compounds are developed and studied for their potential use against multiple myeloma. The compounds are designed to act by a dual mechanism of action, activation of the p53 pathway, and inhibition of the ataxia telangiectasia and Rad3-related protein (ATR). To evaluate the selectivity for the p53 pathway, the compounds are first evaluated in an isogenic pair of HCT116 colon cancer cell lines, with and without p53, and in two breast cancer cell lines expressing different forms of p53. Then, the growth inhibitory effect of the hybrid compounds is tested against the multiple myeloma cell lines RPMI 8226 (mutant p53) and MM.1S (wild-type p53). At the same time, compound 15 is confirmed to inhibit doxorubicin- but not UV-induced DNA damage response via the ATR/Chk1 signaling pathway. The hybrids show lower IC50 values compared to the fragments alone, highlighting the potential for using hybrid molecules containing two pharmacophores with complementary activities. These results suggest that novel hybrid molecules may serve as new leads against multiple myeloma.

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
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
×
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