| Item type |
文献 / Documents(1) |
| 公開日 |
2024-10-29 |
| アクセス権 |
|
|
アクセス権 |
open access |
|
アクセス権URI |
http://purl.org/coar/access_right/c_abf2 |
| 資源タイプ |
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|
資源タイプ識別子 |
http://purl.org/coar/resource_type/c_6501 |
|
資源タイプ |
journal article |
| 出版社版DOI |
|
|
|
識別子タイプ |
DOI |
|
|
関連識別子 |
https://doi.org/10.1038/s41467-023-40385-9 |
|
|
言語 |
ja |
|
|
関連名称 |
10.1038/s41467-023-40385-9 |
| 出版タイプ |
|
|
出版タイプ |
VoR |
|
出版タイプResource |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| タイトル |
|
|
タイトル |
Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation |
|
言語 |
en |
| 著者 |
Yamanaka, Satoshi
Furihata, Hirotake
Yanagihara, Yuta
Taya, Akihito
Nagasaka, Takato
Usui, Mai
Nagaoka, Koya
Shoya, Yuki
Nishino, Kohei
Yoshida, Shuhei
小迫, 英尊
Tanokura, Masaru
Miyakawa, Takuya
Imai, Yuuki
Shibata, Norio
Sawasaki, Tatsuya
|
| 抄録 |
|
|
内容記述タイプ |
Abstract |
|
内容記述 |
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. |
|
言語 |
en |
| 書誌情報 |
en : Nature Communications
巻 14,
p. 4683,
発行日 2023-08-18
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| 収録物ID |
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|
収録物識別子タイプ |
EISSN |
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収録物識別子 |
20411723 |
| 収録物ID |
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|
収録物識別子タイプ |
NCID |
|
収録物識別子 |
AA12645905 |
| 出版者 |
|
|
出版者 |
Springer Nature |
|
言語 |
en |
| 権利情報 |
|
|
言語 |
en |
|
権利情報 |
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. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
| EID |
|
|
識別子 |
409536 |
|
識別子タイプ |
URI |
| 言語 |
|
|
言語 |
eng |
ncomms_14_4683.pdf (2.4 MB)
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