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ID 119205
Title Alternative
In Vivo Protein Knockdown by SNIPER Compound
Author
Ohoka, Nobumichi National Institute of Health Sciences
Okuhira, Keiichiro National Institute of Health Sciences|Tokushima University KAKEN Search Researchers
Ito, Masahiro Takeda Pharmaceutical Co. Ltd.
Nagai, Katsunori Takeda Pharmaceutical Co. Ltd.
Shibata, Norihito National Institute of Health Sciences
Hattori, Takayuki National Institute of Health Sciences
Ujikawa, Osamu Takeda Pharmaceutical Co. Ltd.
Shimokawa, Kenichiro Takeda Pharmaceutical Co. Ltd.
Sano, Osamu Takeda Pharmaceutical Co. Ltd.
Koyama, Ryokichi Takeda Pharmaceutical Co. Ltd.
Fujita, Hisashi Takeda Pharmaceutical Co. Ltd.
Teratani, Mika Takeda Pharmaceutical Co. Ltd.
Matsumoto, Hirokazu Takeda Pharmaceutical Co. Ltd.
Imaeda, Yasuhiro Takeda Pharmaceutical Co. Ltd.
Nara, Hiroshi Takeda Pharmaceutical Co. Ltd.
Cho, Nobuo Takeda Pharmaceutical Co. Ltd.
Naito, Mikihiko National Institute of Health Sciences
Content Type
Journal Article
Description
Many diseases, especially cancers, result from aberrant or overexpression of pathogenic proteins. Specific inhibitors against these proteins have shown remarkable therapeutic effects, but these are limited mainly to enzymes. An alternative approach that may have utility in drug development relies on selective degradation of pathogenic proteins via small chimeric molecules linking an E3 ubiquitin ligase to the targeted protein for proteasomal degradation. To this end, we recently developed a protein knockdown system based on hybrid small molecule SNIPERs (Specific and Nongenetic IAP-dependent Protein Erasers) that recruit inhibitor of the apoptosis protein (IAP) ubiquitin ligases to specifically degrade targeted proteins. Here, we extend our previous study to show a proof of concept of the SNIPER technology in vivo. By incorporating a high affinity IAP ligand, we developed a novel SNIPER against estrogen receptor α (ERα), SNIPER(ER)-87, that has a potent protein knockdown activity. The SNIPER(ER) reduced ERα levels in tumor xenografts and suppressed the growth of ERα-positive breast tumors in mice. Mechanistically, it preferentially recruits X-linked IAP (XIAP) rather than cellular IAP1, to degrade ERα via the ubiquitin-proteasome pathway. With this IAP ligand, potent SNIPERs against other pathogenic proteins, BCR-ABL, bromodomain-containing protein 4 (BRD4), and phosphodiesterase-4 (PDE4) could also be developed. These results indicate that forced ubiquitylation by SNIPERs is a useful method to achieve efficient protein knockdown with potential therapeutic activities and could also be applied to study the role of ubiquitylation in many cellular processes.
Journal Title
Journal of Biological Chemistry
ISSN
1083351X
NCID
AA1202441X
Publisher
American Society for Biochemistry and Molecular Biology|Elsevier
Volume
292
Issue
11
Start Page
4556
End Page
4570
Published Date
2017-02-02
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