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タイトル: | Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation |
著者: | Yamanaka, Satoshi Furihata, Hirotake Yanagihara, Yuta Taya, Akihito Nagasaka, Takato Usui, Mai Nagaoka, Koya Shoya, Yuki Nishino, Kohei Yoshida, Shuhei Kosako, Hidetaka Tanokura, Masaru Miyakawa, Takuya ![]() ![]() ![]() Imai, Yuuki Shibata, Norio Sawasaki, Tatsuya |
著者名の別形: | 山中, 聡士 降旗, 大岳 柳原, 裕太 田谷, 彬人 長坂, 天斗 臼井, 麻衣 長岡, 昂冶 庄屋, 祐希 西野, 耕平 吉田, 周平 小迫, 英尊 田之倉, 優 宮川, 拓也 今井, 祐記 柴田, 哲男 澤崎, 達也 |
キーワード: | Chemical modification Lead optimization Proteolysis Target validation |
発行日: | 18-Aug-2023 |
出版者: | Springer Nature |
誌名: | Nature Communications |
巻: | 14 |
論文番号: | 4683 |
抄録: | 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. |
記述: | 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. |
著作権等: | © The Author(s) 2023 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. |
URI: | http://hdl.handle.net/2433/284738 |
DOI(出版社版): | 10.1038/s41467-023-40385-9 |
PubMed ID: | 37596276 |
関連リンク: | https://www.kyoto-u.ac.jp/ja/research-news/2023-08-21 |
出現コレクション: | 学術雑誌掲載論文等 |
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