The DOI matches its Crossref record; 40 of the 42 references it cites were found in a registry or an index.
In Vivo Knockdown of Pathogenic Proteins via Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent Protein Erasers (SNIPERs)
Open accessAbstract
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.
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“Using this new approach, the authors demonstrated robust degradation of ERα, the chronic myeloid leukemia (CML)-causative BCR–Abl fusion protein, BRD4 and PDE4 proteins in cells [102].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [102]
In the citing paper
“Next-generation PROTACs later derived from more potent peptido-mimetic ligands of IAPs were shown to efficiently induce the knockdown of diverse proteins such as ERα, BCR-ABL, BRD4 or PDE4 (ref. 122 ).”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [122]
In the citing paper
“Inhibitor of apoptosis (IAP) E3 ligases feature a baculoviral IAP repeat (BIR) domain”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [122]
In the citing paper
“that can be exploited for proteolysis targeting chimera (PROTAC) discovery 122 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [122]
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Citations
Cites
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Zhang, J., Yang, P. L., & Gray, N. S. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2559 · Cited by 2,648
IAP family proteins---suppressors of apoptosisPreprint
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Reaching for high-hanging fruit in drug discovery at protein–protein interfaces
Wells, J. A., & McClendon, C. L. (2007) · Nature · doi:10.1038/nature06526 · Cited by 2,002
X-linked IAP is a direct inhibitor of cell-death proteases
Deveraux, Q. L., Takahashi, R., Salvesen, G. S., & Reed, J. C. (1997) · Nature · doi:10.1038/40901 · Cited by 1,956
Phthalimide conjugation as a strategy for in vivo target protein degradation
Winter, G. E., Buckley, D. L., Paulk, J., Roberts, J. M., Souza, A., Dhe-Paganon, S., & Bradner, J. E. (2015) · Science · doi:10.1126/science.aab1433 · Cited by 1,760
IAP proteins: blocking the road to death's door
Salvesen, G. S., & Duckett, C. S. (2002) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm830 · Cited by 1,756
Small-molecule inhibitors of protein–protein interactions: progressing towards the dream
Arkin, M. R., & Wells, J. A. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1343 · Cited by 1,705
Catalytic in vivo protein knockdown by small-molecule PROTACs
Bondeson, D. P., Mares, A., Smith, I. E. D., Ko, E., Campos, S., Miah, A. H., Mulholland, K. E., Routly, N., Buckley, D. L., Gustafson, J. L., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1858 · Cited by 1,356
IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB Activation, and TNFα-Dependent Apoptosis
Varfolomeev, E., Blankenship, J. W., Wayson, S. M., Fedorova, A. V., Kayagaki, N., Garg, P., Zobel, K., Dynek, J. N., Elliott, L. O., Wallweber, H. J. A., et al. (2007) · Cell · doi:10.1016/j.cell.2007.10.030 · Cited by 1,218
Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4
Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., Hines, J., Winkler, J. D., Crew, A. P., Coleman, K., et al. (2015) · Chemistry & Biology · doi:10.1016/j.chembiol.2015.05.009 · Cited by 1,140
Cited by
Sorted by citations
Targeted protein degradation: expanding the toolbox
Schapira, M., Calabrese, M. F., Bullock, A. N., & Crews, C. M. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0047-y · Cited by 960
Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead
Bondeson, D. P., Smith, B. E., Burslem, G. M., Buhimschi, A. D., Hines, J., Jaime-Figueroa, S., Wang, J., Hamman, B. D., Ishchenko, A., & Crews, C. M. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.09.010 · Cited by 923
PROteolysis TArgeting Chimeras (PROTACs) — Past, present and future
Pettersson, M., & Crews, C. M. (2019) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2019.01.002 · Cited by 830
AUTACs: Cargo-Specific Degraders Using Selective Autophagy
Takahashi, D., Moriyama, J., Nakamura, T., Miki, E., Takahashi, E., Sato, A., Akaike, T., Itto-Nakama, K., & Arimoto, H. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.09.009 · Cited by 675
PROTACs: great opportunities for academia and industry
Sun, X., Gao, H., Yang, Y., He, M., Wu, Y., Song, Y.-G., Tong, Y., & Rao, Y. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0101-6 · Cited by 663
Metadata
- Authors
- Ohoka, N., Okuhira, K., Ito, M., Nagai, K., Shibata, N., Hattori, T., Ujikawa, O., Shimokawa, K., Sano, O., Koyama, R., Fujita, H., Teratani, M., Matsumoto, H., Imaeda, Y., Nara, H., Cho, N., & Naito, M.
- Affiliations
- National Institute of Health Sciences (JP)
- Takeda (Japan) (JP)
- Corresponding author
- Naito, Mikihiko
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 292
- Issue
- 11
- Pages
- 4556-4570
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC5377772
- OpenAlex
- W2585495993
- Cited by
- 240
- References
- 42
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 26 · 2023: 21 · 2022: 36 · 2021: 28 · 2020: 41 · 2019: 28 · 2018: 14 · 2017: 18
- FWCI
- 11.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (publishedVersion, cc-by)
- Funders
- Japan Society for the Promotion of Science (26860049, 16H05090, 16K15121)
- Japan Agency for Medical Research and Development (15ak0101029h1402, 16ak0101029j1403, 16cm0106124j0001)
- Takeda Science Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- snipers, protein degradation, inhibitor of apoptosis proteins, XIAP, estrogen receptor alpha, breast cancer, tumor xenografts, ubiquitin-proteasome system, E3 ubiquitin ligase, BCR-ABL, BRD4, phosphodiesterase 4, protein knockdown, targeted protein degradation
- MeSH terms
- Animals, Antineoplastic Agents, Breast, Breast Neoplasms, Cell Line, Female, Humans, Ligands, Mice, Inbred BALB C, Mice, Nude, Cell Line, Tumor, Proteasome Endopeptidase Complex, Estrogen Receptor alpha, Inhibitor of Apoptosis Proteins, Mice, X-Linked Inhibitor of Apoptosis Protein, Small Molecule Libraries, Ubiquitination, Drug Discovery, Proteolysis
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