In VivoKnockdown of Pathogenic Proteins viaSpecific andNongeneticInhibitor of Apoptosis Protein (IAP)-dependentProteinErasers (SNIPERs).
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 andNongeneticIAP-dependentProteinErasers) 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 technologyin vivoBy 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.
From the Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 and.
Nobumichi
N
Ohoka
From the Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 and.
Keiichiro
K
Okuhira
the Medicinal Chemistry Research Laboratories.
Masahiro
M
Ito
the Medicinal Chemistry Research Laboratories.
Katsunori
K
Nagai
From the Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 and.
Norihito
N
Shibata
From the Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 and.
Takayuki
T
Hattori
the Medicinal Chemistry Research Laboratories.
Osamu
O
Ujikawa
the Medicinal Chemistry Research Laboratories.
Kenichiro
K
Shimokawa
Biomolecular Research Laboratories.
Osamu
O
Sano
Biomolecular Research Laboratories.
Ryokichi
R
Koyama
Drug Metabolism and Pharmacokinetics Research Laboratories, and.
Hisashi
H
Fujita
Integrated Technology Research Laboratories.
Mika
M
Teratani
Integrated Technology Research Laboratories.
Hirokazu
H
Matsumoto
Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Yasuhiro
Y
Imaeda
the Medicinal Chemistry Research Laboratories.
Hiroshi
H
Nara
the Medicinal Chemistry Research Laboratories.
Nobuo
N
Cho
From the Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 and miki-naito@nihs.go.jp.
Mikihiko
M
Naito
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D055808:Drug Discovery; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000494:pharmacology / Q000627:therapeutic use*; D054875:Ubiquitination / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
D000970:Antineoplastic Agents; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D051034:Inhibitor of Apoptosis Proteins; D008024:Ligands; D054852:Small Molecule Libraries; D051636:X-Linked Inhibitor of Apoptosis Protein; D046988:Proteasome Endopeptidase Complex
LCL161; SNIPER; X-linked inhibitor of apoptosis protein (XIAP); estrogen receptor; proteasome; tumor therapy; ubiquitin