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ID 119151
タイトル別表記
Development of potent SNIPER derivatives against ERα
著者
Ohoka, Nobumichi National Institute of Health Sciences
Morita, Yoko Takeda Pharmaceutical Co. Ltd.|Axcelead Drug Discovery Partners
Nagai, Katsunori Takeda Pharmaceutical Co. Ltd.|Axcelead Drug Discovery Partners
Shimokawa, Kenichiro Takeda Pharmaceutical Co. Ltd.
Ujikawa, Osamu Takeda Pharmaceutical Co. Ltd.|Axcelead Drug Discovery Partners
Fujimori, Ikuo Takeda Pharmaceutical Co. Ltd.
Ito, Masahiro Takeda Pharmaceutical Co. Ltd.
Hayase, Youji Takeda Pharmaceutical Co. Ltd.
奥平, 桂一郎 National Institute of Health Sciences|Tokushima University KAKEN研究者をさがす
Shibata, Norihito National Institute of Health Sciences
Hattori, Takayuki National Institute of Health Sciences
Sameshima, Tomoya Takeda Pharmaceutical Co. Ltd.
Sano, Osamu Takeda Pharmaceutical Co. Ltd.
Koyama, Ryokichi Takeda Pharmaceutical Co. Ltd.|SCOHIA PHARMA, Inc.
Imaeda, Yasuhiro Takeda Pharmaceutical Co. Ltd.
Nara, Hiroshi Takeda Pharmaceutical Co. Ltd.|The Pharmaceutical Society of Japan
Cho, Nobuo Takeda Pharmaceutical Co. Ltd.|RIKEN
Naito, Mikihiko National Institute of Health Sciences
資料タイプ
学術雑誌論文
抄録
Aberrant expression of proteins often underlies many diseases, including cancer. A recently developed approach in drug development is small molecule-mediated, selective degradation of dysregulated proteins. We have devised a protein-knockdown system that utilizes chimeric molecules termed specific and nongenetic IAP-dependent protein erasers (SNIPERs) to induce ubiquitylation and proteasomal degradation of various target proteins. SNIPER(ER)-87 consists of an inhibitor of apoptosis protein (IAP) ligand LCL161 derivative that is conjugated to the estrogen receptorα (ERα) ligand 4-hydroxytamoxifen by a PEG linker, and we have previously reported that this SNIPER efficiently degrades the ERα protein. Here, we report that derivatization of the IAP ligand module yields SNIPER(ER)s with superior protein-knockdown activity. These improved SNIPER(ER)s exhibited higher binding affinities to IAPs and induced more potent degradation of ERα than does SNIPER(ER)-87. Further, they induced simultaneous degradation of cellular inhibitor of apoptosis protein 1 (cIAP1) and delayed degradation of X-linked IAP (XIAP). Notably, these reengineered SNIPER(ER)s efficiently induced apoptosis in MCF-7 human breast cancer cells that require IAPs for continued cellular survival. We found that one of these molecules, SNIPER(ER)-110, inhibits the growth of MCF-7 tumor xenografts in mice more potently than the previously characterized SNIPER(ER)-87. Mechanistic analysis revealed that our novel SNIPER(ER)s preferentially recruit XIAP, rather than cIAP1, to degrade ERα. Our results suggest that derivatized IAP ligands could facilitate further development of SNIPERs with potent protein knockdown and cytocidal activities against cancer cells requiring IAPs for survival.
掲載誌名
Journal of Biological Chemistry
ISSN
00219258
1083351X
cat書誌ID
AA1202441X
出版者
American Society for Biochemistry and Molecular Biology|Elsevier
293
18
開始ページ
6776
終了ページ
6790
発行日
2018-03-15
権利情報
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
EDB ID
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
出版社版
部局
薬学系