Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 292, Issue 11, Pages 4556-4570Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.768853
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Funding
- Japan Society for the Promotion of Science KAKENHI [26860049, 16H05090, 16K15121]
- Japan Agency for Medical Research and Development [15ak0101029h1402, 16ak0101029j1403, 16cm0106124j0001]
- Ministry of Health and Labor Welfare, Japan
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [16H05090, 16K15121, 26860049] Funding Source: KAKEN
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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 alpha(ER alpha), SNIPER(ER)-87, that has a potent protein knockdown activity. The SNIPER(ER) reduced ER alpha levels in tumor xenografts and suppressed the growth of ER alpha-positive breast tumors in mice. Mechanistically, it preferentially recruits X-linked IAP (XIAP) rather than cellular IAP1, to degrade ER alpha via the ubiquitin-proteasome pathway. With this IAP ligand, potent SNIPERs against other pathogenic proteins, BCR-ABL, bromodo-main- 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.
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