In Vivo Knockdown of Pathogenic Proteins via Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent Protein Erasers (SNIPERs)

• Published in: The Journal of biological chemistry Vol. 292; no. 11; pp. 4556 - 4570
• Main Authors: Ohoka, Nobumichi, Okuhira, Keiichiro, Ito, Masahiro, Nagai, Katsunori, Shibata, Norihito, Hattori, Takayuki, Ujikawa, Osamu, Shimokawa, Kenichiro, Sano, Osamu, Koyama, Ryokichi, Fujita, Hisashi, Teratani, Mika, Matsumoto, Hirokazu, Imaeda, Yasuhiro, Nara, Hiroshi, Cho, Nobuo, Naito, Mikihiko
• Format: Journal Article
• Language: English
• Published: 11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A Elsevier Inc 17.03.2017; American Society for Biochemistry and Molecular Biology
• Subjects: estrogen receptor; LCL161; proteasome; Protein Synthesis and Degradation; SNIPER; tumor therapy; ubiquitin; X-linked inhibitor of apoptosis protein (XIAP); SNIPER; proteasome; LCL161; estrogen receptor; tumor therapy; ubiquitin; X-linked inhibitor of apoptosis protein (XIAP)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M116.768853

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.