Small Molecules Destabilize cIAP1 by Activating Auto-ubiquitylation
Open accessAbstract
Overexpression of an anti-apoptotic protein cIAP1 caused by its genetic amplification was reported in certain cancers, such as hepatocellular carcinoma, esophageal squamous cell carcinoma, cervical cancer, and lung cancer, which confers resistance to chemotherapy and radiotherapy. Here we report cIAP1 to be selectively down-regulated by a class of small molecules ((-)-N-[(2S,3R)-3-amino-2-hydroxy-4-phenyl-butyryl]-l-leucine methyl ester (ME-BS)), resulting in a sensitization of cancer cells to apoptosis. ME-BS directly interacts with the BIR3 domain of cIAP1, promotes auto-ubiquitylation dependent on its RING domain, and facilitates proteasomal degradation of cIAP1. Other IAPs such as XIAP and cIAP2 were not affected by ME-BS. These results suggest targeted destabilization of cIAP1 by small molecules as a novel method to treat cancers expressing cIAP1, which interferes with treatment. Manipulation of the intrinsic ubiquitin-ligase activity could be a novel strategy to develop small molecules for therapeutic purposes.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Methyl-bestatin (ME-BS) is a potent binder of c-IAP1, which induces autoubiquitination and degradation of c-IAP1 by binding its BIR3 domain.
“A decade ago, methyl-bestatin (ME-BS) was identified as a potent binder of c-IAP1, which induced autoubiquitination and degradation of c-IAP1 by binding its BIR3 domain [98].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [98]
Bestatin binds BIRC2 with moderate affinity and induces its auto-ubiquitylation and degradation.
“bestatin, which binds BIRC2 with moderate affinity and induces its auto-ubiquitylation and degradation”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [121]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Du, C., Fang, M., Li, Y., Li, L., & Wang, X. (2000) · Cell · doi:10.1016/s0092-8674(00)00008-8 · Cited by 3,513 · see citing works
Mitochondrial control of cell death
Kroemer, G., & Reed, J. C. (2000) · Nature Medicine · doi:10.1038/74994 · Cited by 3,103 · see citing works
IAP family proteins---suppressors of apoptosisPreprint
Deveraux, Q. L., & Reed, J. C. (1999) · Genes & Development · doi:10.1101/gad.13.3.239 · Cited by 2,535 · see citing works
(2001) · PubMed · Cited by 2,381 · see citing works
Verhagen, A. M., Ekert, P. G., Pakusch, M., Silke, J., Connolly, L. M., Reid, G. E., Moritz, R. L., Simpson, R. J., & Vaux, D. L. (2000) · Cell · doi:10.1016/s0092-8674(00)00009-x · Cited by 2,372 · see citing works
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 · see citing works
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 · see citing works
The c‐IAP‐1 and c‐IAP‐2 proteins are direct inhibitors of specific caspases
Roy, N., Deveraux, Q. L., Takahashi, R., Salvesen, G. S., & Reed, J. C. (1997) · The EMBO Journal · doi:10.1093/emboj/16.23.6914 · Cited by 1,302 · see citing works
Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach
Zender, L., Spector, M. S., Xue, W., Flemming, P., Cordon-Cardo, C., Silke, J., Fan, S.-T., Luk, J. M., Wigler, M., Hannon, G. J., et al. (2006) · Cell · doi:10.1016/j.cell.2006.05.030 · Cited by 1,065 · see citing works
Srinivasula, S. M., Hegde, R. P., Saleh, A., Datta, P., Shiozaki, E. N., Chai, J., Lee, R., Robbins, P. D., Fernandes‐Alnemri, T., Shi, Y., et al. (2001) · Nature · doi:10.1038/35065125 · Cited by 1,013 · see citing works
Yang, Y., Fang, S., Jensen, J. P., Weissman, A. M., & Ashwell, J. D. (2000) · Science · doi:10.1126/science.288.5467.874 · Cited by 981 · see citing works
Suzuki, Y., Nakabayashi, Y., & Takahashi, R. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.161506698 · Cited by 654 · see citing works
A Small Molecule Smac Mimic Potentiates TRAIL- and TNFα-Mediated Cell Death
Li, L., Thomas, R., Suzuki, H., Brabander, J. D., Wang, X.-D., & Harran, P. G. (2004) · Science · doi:10.1126/science.1098231 · Cited by 620 · see citing works
IAPs, RINGs and ubiquitylation
Vaux, D. L., & Silke, J. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1621 · Cited by 611 · see citing works
Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias.
Tamm, I., Kornblau, S. M., Segall, H., Krajewski, S., Welsh, K., Kitada, S., Scudiero, D. A., Tudor, G., Qui, Y. H., Monks, A. P., et al. (2000) · PubMed · Cited by 610 · see citing works
A Single BIR Domain of XIAP Sufficient for Inhibiting Caspases
Takahashi, R., Deveraux, Q. L., Tamm, I., Welsh, K., Assa‐Munt, N., Salvesen, G. S., & Reed, J. C. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.14.7787 · Cited by 608 · see citing works
Livin, a Novel Inhibitor of Apoptosis Protein Family Member
Kasof, G. M., & Gomes, B. C. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m003670200 · Cited by 455 · see citing works
ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas
Vucic, D., Stennicke, H. R., Pisabarro, M. T., Salvesen, G. S., & Dixit, V. M. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00781-8 · Cited by 413 · see citing works
Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity
Schimmer, A. D., Welsh, K., Pinilla, C., Wang, Z., Krajewska, M., Bonneau, M.-J., Pedersen, I. M., Kitada, S., Scott, F. L., Bailly‐Maitre, B., et al. (2004) · Cancer Cell · doi:10.1016/s1535-6108(03)00332-5 · Cited by 411 · see citing works
The Human Anti-apoptotic Proteins cIAP1 and cIAP2 Bind but Do Not Inhibit Caspases
Eckelman, B. P., & Salvesen, G. S. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m510863200 · Cited by 391 · see citing works
Discovery of Potent Antagonists of the Antiapoptotic Protein XIAP for the Treatment of Cancer
Oost, T. K., Sun, C. C., Armstrong, R. C., Al-Assaad, A.-S., Betz, S. F., Deckwerth, T. L., Ding, H., Elmore, S. W., Meadows, R. P., Olejniczak, E. T., et al. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm040037k · Cited by 367 · see citing works
Elevated expression of inhibitor of apoptosis proteins in prostate cancer.
Krajewska, M., Krajewski, S., Banares, S., et al. (2003) · PubMed · Cited by 250 · see citing works
Apollon ubiquitinates SMAC and caspase-9, and has an essential cytoprotection function
Hao, Y., Sekine, K., Kawabata, A., Nakamura, H., Ishioka, T., Ohata, H., Katayama, R., Hashimoto, C., Zhang, X., Noda, T., et al. (2004) · Nature Cell Biology · doi:10.1038/ncb1159 · Cited by 243 · see citing works
Self-citationDual Role of BRUCE as an Antiapoptotic IAP and a Chimeric E2/E3 Ubiquitin Ligase
Bartke, T., Pohl, C., Pyrowolakis, G., & Jentsch, S. (2004) · Molecular Cell · doi:10.1016/j.molcel.2004.05.018 · Cited by 222 · see citing works
A Human IAP-Family Gene, Apollon, Expressed in Human Brain Cancer Cells
Chen, Z., Naito, M., Hori, S., et al. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.1585 · Cited by 219 · see citing works
Self-citationImoto, I., Yang, Z.-Q., Pimkhaokham, A., Tsuda, H., Shimada, Y., Imamura, M., Ohki, M., & Inazawa, J. (2001) · PubMed · Cited by 213 · see citing works
Yang, Q.-H., & Du, C. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m401253200 · Cited by 213 · see citing works
Posttranscriptional Downregulation of c-IAP2 by the Ubiquitin Protein Ligase c-IAP1 In Vivo
Conze, D. B., Albert, L., Ferrick, D. A., Goeddel, D. V., Yeh, W., Mak, T. W., & Ashwell, J. D. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.8.3348-3356.2005 · Cited by 186 · see citing works
ASK1 mediates apoptotic cell death induced by genotoxic stress
Chen, Z., Seimiya, H., Naito, M., Mashima, T., Kizaki, A., Dan, S., Imaizumi, M., Ichijo, H., Miyazono, K., & Tsuruo, T. (1999) · Oncogene · doi:10.1038/sj.onc.1202276 · Cited by 177 · see citing works
Self-citationZobel, K., Wang, L., Varfolomeev, E. E., Franklin, M. C., Elliott, L. O., Wallweber, H. J. A., Okawa, D. C., Flygare, J. A., Vucic, D., Fairbrother, W. J., et al. (2006) · ACS Chemical Biology · doi:10.1021/cb600276q · Cited by 175 · see citing works
Synthesis and structure-activity relations of bestatin analogs, inhibitors of aminopeptidase B
NISHIZAWA, R., Saino, T., TAKITA, T., et al. (1977) · Journal of Medicinal Chemistry · doi:10.1021/jm00214a010 · Cited by 165 · see citing works
Dai, Z. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg083 · Cited by 164 · see citing works
Imoto, I., Tsuda, H., Hirasawa, A., Miura, M., Sakamoto, M., Hirohashi, S., & Inazawa, J. (2002) · PubMed · Cited by 154 · see citing works
Sun, H., Nikolovska‐Coleska, Z., Yang, C., Xu, L., Tomita, Y. A., Krajewski, K., Roller, P. P., & Wang, S. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm0499108 · Cited by 131 · see citing works
Ichinose, Y., Genka, K., Koike, T., et al. (2003) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/95.8.605 · Cited by 116 · see citing works
Ferreira, C. G., van der Valk, P., Span, S. W., et al. (2001) · Annals of Oncology · doi:10.1023/a:1011167113067 · Cited by 105 · see citing works
Immunomodulatory and therapeutic properties of bestatin in mice.
Talmadge, J. E., Lenz, B. F., Pennington, R., et al. (1986) · PubMed · Cited by 89 · see citing works
Induction of apoptosis by bestatin (ubenimex) in human leukemic cell lines
Sekine, K., Fujii, H., & Abe, F. (1999) · Leukemia · doi:10.1038/sj.leu.2401388 · Cited by 86 · see citing works
Self-citationHunter, A. M., Kottachchi, D., Lewis, J., Duckett, C. S., Korneluk, R. G., & Liston, P. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c200695200 · Cited by 54 · see citing works
Adjuvant effect of Ubenimex on a DNA vaccine for HIV-1
Sasaki, S., Fukushima, J., Hamajima, K., et al. (1998) · Clinical & Experimental Immunology · doi:10.1046/j.1365-2249.1998.00466.x · Cited by 44 · see citing works
Sekine, K., Fujii, H., Abe, F., et al. (2001) · International Journal of Cancer · doi:10.1002/ijc.1492 · Cited by 43 · see citing works
Self-citationEffects of bestatin on myelopoietic stem cells in normal and cyclophosphamide-treated mice
Abe, F., Matsuda, A., Schneider, M., et al. (1990) · Cancer Immunology Immunotherapy · doi:10.1007/bf01754202 · Cited by 12 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Suzuki, Y., Nakabayashi, Y., and Takahashi, R. (2001) Proc. Natl. Acad. Sci.
Cited by
Sorted by citations
Induced protein degradation: an emerging drug discovery paradigm
Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486 · see citing works
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 · see citing works
Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery
Burslem, G. M., & Crews, C. M. (2020) · Cell · doi:10.1016/j.cell.2019.11.031 · Cited by 1,079 · see citing works
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 · see citing works
Small‐Molecule PROTACS: New Approaches to Protein Degradation
Toure, M., & Crews, C. M. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201507978 · Cited by 674 · see citing works
A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader
Huang, H.-T., Dobrovolsky, D., Paulk, J., Yang, G., Weisberg, E. L., Doctor, Z. M., Buckley, D. L., Cho, J.-H., Ko, E., Jang, J., et al. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.10.005 · Cited by 437 · see citing works
Itoh, Y., Ishikawa, M., Naito, M., & Hashimoto, Y. (2010) · Journal of the American Chemical Society · doi:10.1021/ja100691p · Cited by 404 · see citing works
Self-citationHines, J., Lartigue, S., Dong, H., Qian, Y., & Crews, C. M. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-2918 · Cited by 348 · see citing works
Degradation of proteins by PROTACs and other strategies
Wang, Y., Jiang, X., Feng, F., Liu, W., & Sun, H. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2019.08.001 · Cited by 335 · see citing works
Chemistries of bifunctional PROTAC degraders
Cao, C., He, M., Wang, L., He, Y., & Rao, Y. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00220e · Cited by 313 · see citing works
Waste disposal—An attractive strategy for cancer therapy
Salami, J., & Crews, C. M. (2017) · Science · doi:10.1126/science.aam7340 · Cited by 279 · see citing works
Ohoka, N., Okuhira, K., Ito, M., Nagai, K., Shibata, N., Hattori, T., Ujikawa, O., Shimokawa, K., Sano, O., Koyama, R., et al. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.768853 · Cited by 240 · see citing works
Self-citationPROTACs: An Emerging Targeting Technique for Protein Degradation in Drug Discovery
Gu, S., Cui, D., Chen, X., Xiong, X., & Zhao, Y. (2018) · BioEssays · doi:10.1002/bies.201700247 · Cited by 231 · see citing works
Targeted Protein Degradation by Small Molecules
Bondeson, D. P., & Crews, C. M. (2017) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010715-103507 · Cited by 207 · see citing works
PROTAC-Mediated Degradation of Bruton’s Tyrosine Kinase Is Inhibited by Covalent Binding
Tinworth, C. P., Lithgow, H., Dittus, L., Bassi, Z. I., Hughes, S. E., Muelbaier, M., Dai, H., Smith, I. E. D., Kerr, W. J., Burley, G. A., et al. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.8b01094 · Cited by 195 · see citing works
Discovery of Small Molecules that Induce the Degradation of Huntingtin
Tomoshige, S., Nomura, S., Ohgane, K., Hashimoto, Y., & Ishikawa, M. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201706529 · Cited by 144 · see citing works
Ligandability of E3 Ligases for Targeted Protein Degradation Applications
Belcher, B. P., Ward, C. C., & Nomura, D. K. (2023) · Biochemistry · doi:10.1021/acs.biochem.1c00464 · Cited by 132 · see citing works
Okuhira, K., Ohoka, N., Sai, K., Nishimaki-Mogami, T., Itoh, Y., Ishikawa, M., Hashimoto, Y., & Naito, M. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.03.019 · Cited by 118 · see citing works
Self-citationSnapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes
Schiemer, J., Horst, R., Meng, Y., Montgomery, J. I., Xu, Y., Feng, X., Borzilleri, K., Uccello, D. P., Leverett, C., Brown, S., et al. (2021) · Nature Chemical Biology · doi:10.1038/s41589-020-00686-2 · Cited by 113 · see citing works
Advances in targeted degradation of endogenous proteins
Röth, S., Fulcher, L. J., & Sapkota, G. P. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03112-6 · Cited by 92 · see citing works
A critical evaluation of the approaches to targeted protein degradation for drug discovery
Chopra, R., Sadok, A., & Collins, I. (2019) · Drug Discovery Today: Technologies · doi:10.1016/j.ddtec.2019.02.002 · Cited by 53 · see citing works
Niedermolekulare PROTACs: neue Wege zum Abbau von Proteinen
Toure, M., & Crews, C. M. (2016) · Angewandte Chemie · doi:10.1002/ange.201507978 · Cited by 40 · see citing works
- Authors
- Sekine, K., Takubo, K., Kikuchi, R., Nishimoto, M., Kitagawa, M., Abe, F., Nishikawa, K., Tsuruo, T., & Naito, M.
- Affiliations
- Nippon Kayaku (Japan) (JP)
- The University of Tokyo (JP)
- Japanese Foundation For Cancer Research (JP)
- Corresponding author
- Naito, Mikihiko
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-04
- Volume
- 283
- Issue
- 14
- Pages
- 8961-8968
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1986231077
- Cited by
- 173
- References
- 42
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 13 · 2023: 14 · 2022: 26 · 2021: 12 · 2020: 13 · 2019: 19 · 2018: 11 · 2017: 13 · 2016: 11 · 2015: 6 · 2014: 4 · 2013: 3 · 2012: 4
- FWCI
- 1.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- cIAP1, inhibitor of apoptosis proteins, small molecule inhibitors, BIR3 domain, RING domain, proteasomal degradation, apoptosis sensitization, XIAP, cIAP2, chemoresistance, radiotherapy resistance, ubiquitin ligase activity, cancer therapy
- MeSH terms
- Antineoplastic Agents, HeLa Cells, Humans, Leucine, Neoplasms, Gene Expression Regulation, Neoplastic, Apoptosis, Protein Structure, Tertiary, Drug Resistance, Neoplasm, Ubiquitin, Proteasome Endopeptidase Complex, Inhibitor of Apoptosis Proteins, Ubiquitination
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
