Targeting IAP proteins for therapeutic intervention in cancer
Open accessAbstract
Evasion of apoptosis is one of the crucial acquired capabilities used by cancer cells to fend off anticancer therapies. Inhibitor of apoptosis (IAP) proteins exert a range of biological activities that promote cancer cell survival and proliferation. X chromosome-linked IAP is a direct inhibitor of caspases - pro-apoptotic executioner proteases - whereas cellular IAP proteins block the assembly of pro-apoptotic protein signalling complexes and mediate the expression of anti-apoptotic molecules. Furthermore, mutations, amplifications and chromosomal translocations of IAP genes are associated with various malignancies. Among the therapeutic strategies that have been designed to target IAP proteins, the most widely used approach is based on mimicking the IAP-binding motif of second mitochondria-derived activator of caspase (SMAC), which functions as an endogenous IAP antagonist. Alternative strategies include transcriptional repression and the use of antisense oligonucleotides. This Review provides an update on IAP protein biology as well as current and future perspectives on targeting IAP proteins for therapeutic intervention in human malignancies.
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In presence of SMAC mimetics, RIPK1 is deubiquitinated by CYLD, favoring release from complex I and association with FADD and CASP8 in cytosol to form complex II, which drives extrinsic apoptosis.
“Conversely, in the presence of so-called “SMAC mimetics” (which de facto operate as IAP inhibitors) [337], RIPK1 is deubiquitinated by CYLD lysine 63 deubiquitinase (CYLD), favoring its release from complex I and its association with FADD and CASP8 in the cytosol to form complex II, which drives extrinsic apoptosis [338].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [337]
Small-molecule antagonists exploiting the substrate-binding site of IAPs, including non-peptido-mimetic compounds, have been developed with low-nanomolar potency.
“small-molecule antagonists exploiting the substrate-binding site, including non-peptido-mimetic compounds, have been developed with low-nanomolar potency 117,118,119”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [119]
Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590 · see citing works
Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(00)00129-0 · Cited by 18,139 · 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
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 · see citing works
SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex
Tokunaga, F., Nakagawa, T., Nakahara, M., Saeki, Y., Taniguchi, M., Sakata, S.-I., Tanaka, K., Nakano, H., & Iwai, K. (2011) · Nature · doi:10.1038/nature09815 · Cited by 609 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Self-citationInactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice
Friedmann Angeli, J. P., Schneider, M., Proneth, B., Tyurina, Y. Y., Tyurin, V. A., Hammond, V. J., Herbach, N., Aichler, M., Walch, A., Eggenhofer, E., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb3064 · Cited by 3,732 · see citing works
Small-Molecule Inhibitors of Protein-Protein Interactions: Progressing toward the Reality
Arkin, M. R., Tang, Y., & Wells, J. A. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.09.001 · Cited by 1,065 · 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
HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins
Buckley, D. L., Raina, K., Darricarrere, N., Hines, J., Gustafson, J. L., Smith, I. E., Miah, A. H., Harling, J. D., & Crews, C. M. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00442 · Cited by 488 · see citing works
A fate worse than death: apoptosis as an oncogenic process
Ichim, G., & Tait, S. W. G. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.58 · Cited by 451 · see citing works
Drugging the undruggables: exploring the ubiquitin system for drug development
Huang, X., & Dixit, V. M. (2016) · Cell Research · doi:10.1038/cr.2016.31 · Cited by 427 · 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
Oncogenic protein interfaces: small molecules, big challenges
Nero, T. L., Morton, C. J., Holien, J. K., Wielens, J., & Parker, M. W. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3690 · Cited by 312 · see citing works
Cell-to-cell variation in p53 dynamics leads to fractional killing.
Paek, A. L., Liu, J. C., Loewer, A., Forrester, W. C., & Lahav, G. (2016) · Cell · doi:10.1016/j.cell.2016.03.025 · Cited by 292 · 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
Dufva, O., Koski, J., Maliniemi, P., Ianevski, A., Klievink, J., Leitner, J., Pölönen, P., Hohtari, H., Saeed, K., Hannunen, T., et al. (2020) · Blood · doi:10.1182/blood.2019002121 · Cited by 224 · see citing works
Infante, J. R., Dees, E. C., Olszanski, A. J., Dhuria, S. V., Sen, S., Cameron, S., & Cohen, R. B. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2013.52.3993 · Cited by 210 · see citing works
Harnessing the Power of Proteolysis for Targeted Protein Inactivation
Verma, R., Mohl, D., & Deshaies, R. J. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.01.010 · Cited by 185 · see citing works
Targeting Class I Histone Deacetylases in a “Complex” Environment
Millard, C. J., Watson, P. J., Fairall, L., & Schwabe, J. W. R. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.12.006 · Cited by 180 · see citing works
Drug Resistance in Colorectal Cancer: From Mechanism to Clinic
Wang, Q., Shen, X., Chen, G., & Du, J. (2022) · Cancers · doi:10.3390/cancers14122928 · Cited by 160 · see citing works
Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer
He, S., Ma, J., Fang, Y., Liu, Y., Wu, S., Dong, G., Wang, W., & Sheng, C. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.11.022 · Cited by 91 · see citing works
Chessari, G., Buck, I. M., Day, J. E. H., Day, P. J., Iqbal, A., Johnson, C. N., Lewis, E. J., Martins, V., Miller, D., Reader, M., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00706 · Cited by 90 · see citing works
Small molecule modulators of protein-protein interactions: selected case studies
Aeluri, M., Chamakuri, S., Dasari, B., Guduru, S. K. R., Jimmidi, R., Jogula, S., & Arya, P. (2014) · Chemical Reviews · doi:10.1021/cr4004049 · Cited by 79 · see citing works
Tamanini, E., Buck, I. M., Chessari, G., Chiarparin, E., Day, J. E. H., Frederickson, M., Griffiths-Jones, C. M., Hearn, K., Heightman, T. D., Iqbal, A., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01877 · Cited by 72 · see citing works
Small molecules targeting protein–protein interactions for cancer therapy
Wu, D., Li, Y., Zheng, L., Xiao, H., Ouyang, L., Wang, G., & Sun, Q. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.05.035 · Cited by 71 · see citing works
Immunotherapies targeting stimulatory pathways and beyond
Marin-Acevedo, J. A., Kimbrough, E. O., Manochakian, R., Zhao, Y., & Lou, Y. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01085-3 · Cited by 52 · see citing works
Therapeutics Targeting the Core Apoptotic Machinery
Hamilton, C., Fox, J. P., Longley, D. B., & Higgins, C. A. (2021) · Cancers · doi:10.3390/cancers13112618 · Cited by 26 · see citing works
Oral proteasome inhibitor with strong preclinical efficacy in myeloma models
Park, J., Park, E., Jung, C.-K., Kang, S.-W., Kim, B. G., Jung, Y., Kim, T. H., Lim, J.-Y., Lee, S.-E., Min, C.-K., et al. (2016) · BMC Cancer · doi:10.1186/s12885-016-2285-2 · Cited by 9 · see citing works
- Authors
- Fulda, S., & Vucic, D.
- Affiliations
- Goethe University Frankfurt (DE)
- Genentech (US)
- Corresponding author
- Fulda, Simone
- Vucic, Domagoj
- Venue
- Nature Reviews Drug Discovery
- Published
- 2012-02
- Volume
- 11
- Issue
- 2
- Pages
- 109-124
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- OpenAlex
- W2091269867
- Cited by
- 837
- References
- 5
- Citations by year
- 2026: 30 · 2025: 29 · 2024: 35 · 2023: 39 · 2022: 52 · 2021: 53 · 2020: 62 · 2019: 55 · 2018: 72 · 2017: 61 · 2016: 81 · 2015: 73 · 2014: 84 · 2013: 70 · 2012: 39
- FWCI
- 7.90
- Type
- journal article
- Language
- en
- Update notices
- erratum (2012-03-30)
- Open access
- green
- zenodo.org
- Licence
- Locations
- Nature Reviews Drug Discovery (publishedVersion)
- PubMed (publishedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- inhibitor of apoptosis proteins, IAP antagonists, apoptosis evasion, cancer therapy, caspase inhibition, Smac/DIABLO, chromosomal translocation, transcriptional repression, antisense oligonucleotides, anticancer drug development
- MeSH terms
- Animals, Antineoplastic Agents, Drug Therapy, Combination, Humans, Neoplasms, Signal Transduction, Cell Death, Apoptosis, Oligodeoxyribonucleotides, Antisense, Inhibitor of Apoptosis Proteins, X-Linked Inhibitor of Apoptosis Protein
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