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dc.contributor.author | Yamanaka, Satoshi | en |
dc.contributor.author | Furihata, Hirotake | en |
dc.contributor.author | Yanagihara, Yuta | en |
dc.contributor.author | Taya, Akihito | en |
dc.contributor.author | Nagasaka, Takato | en |
dc.contributor.author | Usui, Mai | en |
dc.contributor.author | Nagaoka, Koya | en |
dc.contributor.author | Shoya, Yuki | en |
dc.contributor.author | Nishino, Kohei | en |
dc.contributor.author | Yoshida, Shuhei | en |
dc.contributor.author | Kosako, Hidetaka | en |
dc.contributor.author | Tanokura, Masaru | en |
dc.contributor.author | Miyakawa, Takuya | en |
dc.contributor.author | Imai, Yuuki | en |
dc.contributor.author | Shibata, Norio | en |
dc.contributor.author | Sawasaki, Tatsuya | en |
dc.contributor.alternative | 山中, 聡士 | ja |
dc.contributor.alternative | 降旗, 大岳 | ja |
dc.contributor.alternative | 柳原, 裕太 | ja |
dc.contributor.alternative | 田谷, 彬人 | ja |
dc.contributor.alternative | 長坂, 天斗 | ja |
dc.contributor.alternative | 臼井, 麻衣 | ja |
dc.contributor.alternative | 長岡, 昂冶 | ja |
dc.contributor.alternative | 庄屋, 祐希 | ja |
dc.contributor.alternative | 西野, 耕平 | ja |
dc.contributor.alternative | 吉田, 周平 | ja |
dc.contributor.alternative | 小迫, 英尊 | ja |
dc.contributor.alternative | 田之倉, 優 | ja |
dc.contributor.alternative | 宮川, 拓也 | ja |
dc.contributor.alternative | 今井, 祐記 | ja |
dc.contributor.alternative | 柴田, 哲男 | ja |
dc.contributor.alternative | 澤崎, 達也 | ja |
dc.date.accessioned | 2023-08-22T06:15:47Z | - |
dc.date.available | 2023-08-22T06:15:47Z | - |
dc.date.issued | 2023-08-18 | - |
dc.identifier.uri | http://hdl.handle.net/2433/284738 | - |
dc.description | 催奇性を回避できるサリドマイドの改良とPROTACへの応用 --重篤な副作用を軽減したタンパク質分解誘導剤開発への第一歩--. 京都大学プレスリリース. 2023-08-21. | ja |
dc.description.abstract | Lenalidomide, an immunomodulatory drug (IMiD), is commonly used as a first-line therapy in many haematological cancers, such as multiple myeloma (MM) and 5q myelodysplastic syndromes (5q MDS), and it functions as a molecular glue for the protein degradation of neosubstrates by CRL4CRBN. Proteolysis-targeting chimeras (PROTACs) using IMiDs with a target protein binder also induce the degradation of target proteins. The targeted protein degradation (TPD) of neosubstrates is crucial for IMiD therapy. However, current IMiDs and IMiD-based PROTACs also break down neosubstrates involved in embryonic development and disease progression. Here, we show that 6-position modifications of lenalidomide are essential for controlling neosubstrate selectivity; 6-fluoro lenalidomide induced the selective degradation of IKZF1, IKZF3, and CK1α, which are involved in anti-haematological cancer activity, and showed stronger anti-proliferative effects on MM and 5q MDS cell lines than lenalidomide. PROTACs using these lenalidomide derivatives for BET proteins induce the selective degradation of BET proteins with the same neosubstrate selectivity. PROTACs also exert anti-proliferative effects in all examined cell lines. Thus, 6-position-modified lenalidomide is a key molecule for selective TPD using thalidomide derivatives and PROTACs. | en |
dc.language.iso | eng | - |
dc.publisher | Springer Nature | en |
dc.rights | © The Author(s) 2023 | en |
dc.rights | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. | en |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | - |
dc.subject | Chemical modification | en |
dc.subject | Lead optimization | en |
dc.subject | Proteolysis | en |
dc.subject | Target validation | en |
dc.title | Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation | en |
dc.type | journal article | - |
dc.type.niitype | Journal Article | - |
dc.identifier.jtitle | Nature Communications | en |
dc.identifier.volume | 14 | - |
dc.relation.doi | 10.1038/s41467-023-40385-9 | - |
dc.textversion | publisher | - |
dc.identifier.artnum | 4683 | - |
dc.address | Division of Cell-Free Sciences, Proteo-Science Center, Ehime University; Division of Proteo-Interactome, Proteo-Science Center, Ehime University | en |
dc.address | Division of Cell-Free Sciences, Proteo-Science Center, Ehime University; Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo | en |
dc.address | Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University | en |
dc.address | Department of Life Science and Applied Chemistry, Nagoya Institute of Technology | en |
dc.address | Department of Life Science and Applied Chemistry, Nagoya Institute of Technology | en |
dc.address | Department of Life Science and Applied Chemistry, Nagoya Institute of Technology | en |
dc.address | Division of Cell-Free Sciences, Proteo-Science Center, Ehime University | en |
dc.address | Division of Cell-Free Sciences, Proteo-Science Center, Ehime University | en |
dc.address | Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Tokushima University | en |
dc.address | Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University | en |
dc.address | Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Tokushima University | en |
dc.address | Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo | en |
dc.address | Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo; Graduate School of Biostudies, Kyoto University | en |
dc.address | Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University | en |
dc.address | Department of Life Science and Applied Chemistry, Nagoya Institute of Technology | en |
dc.address | Division of Cell-Free Sciences, Proteo-Science Center, Ehime University | en |
dc.identifier.pmid | 37596276 | - |
dc.relation.url | https://www.kyoto-u.ac.jp/ja/research-news/2023-08-21 | - |
dcterms.accessRights | open access | - |
datacite.awardNumber | 21H00285 | - |
datacite.awardNumber | 16H06579 | - |
datacite.awardNumber | 19H04966 | - |
datacite.awardNumber | 21K15076 | - |
datacite.awardNumber | 19H03218 | - |
datacite.awardNumber | 17H06112 | - |
datacite.awardNumber.uri | https://kaken.nii.ac.jp/grant/KAKENHI-PUBLICLY-21H00285/ | - |
datacite.awardNumber.uri | https://kaken.nii.ac.jp/grant/KAKENHI-PLANNED-16H06579/ | - |
datacite.awardNumber.uri | https://kaken.nii.ac.jp/grant/KAKENHI-PUBLICLY-19H04966/ | - |
datacite.awardNumber.uri | https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21K15076/ | - |
datacite.awardNumber.uri | https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-19H03218/ | - |
datacite.awardNumber.uri | https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17H06112/ | - |
dc.identifier.pissn | 2041-1723 | - |
jpcoar.funderName | 日本学術振興会 | ja |
jpcoar.funderName | 日本学術振興会 | ja |
jpcoar.funderName | 日本学術振興会 | ja |
jpcoar.funderName | 日本学術振興会 | ja |
jpcoar.funderName | 日本学術振興会 | ja |
jpcoar.funderName | 日本学術振興会 | ja |
jpcoar.awardTitle | 近接ビオチン化酵素を用いたPROTAC依存的なインタラクトーム解析技術の開発 | ja |
jpcoar.awardTitle | 分子間相互作用に基づくシグナル伝達網解析のための無細胞プロテオーム技術の開発 | ja |
jpcoar.awardTitle | 自然免疫分子STINGを介したシグナル伝達経路の重層的プロテオーム解析 | ja |
jpcoar.awardTitle | 近接ビオチン化酵素を用いたサリドマイドのインタラクトーム解析技術の開発 | ja |
jpcoar.awardTitle | 無細胞ヒトプロテインアレイを用いた薬剤依存的相互作用タンパク質同定技術の開発 | ja |
jpcoar.awardTitle | 脳神経幹細胞の増殖分化を制御するサリドマイド標的因子セレブロンの新規作動薬の探索 | ja |
出現コレクション: | 学術雑誌掲載論文等 |
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