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ID 119151
Title Alternative
Development of potent SNIPER derivatives against ERα
Author
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.
Okuhira, Keiichiro National Institute of Health Sciences|Tokushima University KAKEN Search Researchers
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
Content Type
Journal Article
Description
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.
Journal Title
Journal of Biological Chemistry
ISSN
00219258
1083351X
NCID
AA1202441X
Publisher
American Society for Biochemistry and Molecular Biology|Elsevier
Volume
293
Issue
18
Start Page
6776
End Page
6790
Published Date
2018-03-15
Rights
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
Publisher
departments
Pharmaceutical Sciences