Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization
Open accessAbstract
Activation of p53 tumor suppressor by antagonizing its negative regulator murine double minute (MDM)2 has been considered an attractive strategy for cancer therapy and several classes of p53-MDM2 binding inhibitors have been developed. However, these compounds do not inhibit the p53-MDMX interaction, and their effectiveness can be compromised in tumors overexpressing MDMX. Here, we identify small molecules that potently block p53 binding with both MDM2 and MDMX by inhibitor-driven homo- and/or heterodimerization of MDM2 and MDMX proteins. Structural studies revealed that the inhibitors bind into and occlude the p53 pockets of MDM2 and MDMX by inducing the formation of dimeric protein complexes kept together by a dimeric small-molecule core. This mode of action effectively stabilized p53 and activated p53 signaling in cancer cells, leading to cell cycle arrest and apoptosis. Dual MDM2/MDMX antagonists restored p53 apoptotic activity in the presence of high levels of MDMX and may offer a more effective therapeutic modality for MDMX-overexpressing cancers.
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This suggests that the disruption of p53-MDMX, rather than p53-MDM2, complexes may contribute to its cellular efficacy.
“This suggests that the disruption of p53–MDMX, rather than p53–MDM2, complexes may contribute to its cellular efficacy103.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [103]
In contrast to nutlin 3a, RO-5963 kills cells with both high MDM2 levels and high MDMX levels.
“Furthermore, in contrast to nutlin 3a, RO-5963 kills cells with both high MDM2 levels and high MDMX levels.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [103]
RO-5963 was identified as a dual inhibitor of p53-MDM2 and p53-MDMX.
“RO-5963 was identified as a dual inhibitor of p53–MDM2 and p53–MDMX103.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [103]
Subtle structural differences in the MDMX N-terminal p53-binding pocket dramatically reduce the binding affinity of both nutlin 3a and MI-219 for MDMX; nutlin 3a is 500-fold less potent against MDMX compared with MDM2.
“However, subtle structural differences in the MDMX N-terminal p53-binding pocket dramatically reduce the binding affinity of both nutlin 3a and MI-219 for MDMX; this is supported by in vitro binding studies showing that nutlin 3a is 500-fold less potent against MDMX compared with MDM2 (Ref. 103).”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [103]
RO2443 prevents MDMX binding to p53 by stabilizing an inactive MDMX homodimer.
“Additional examples are RO2443, which prevents MDMX binding to p53 by stabilizing an inactive MDMX homodimer, 108”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [108]
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Cites
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661 · see citing works
Self-citationMomand, J., Zambetti, G. P., Olson, D. C., George, D., & Levine, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90644-r · Cited by 3,113 · see citing works
Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain
Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J., & Pavletich, N. P. (1996) · Science · doi:10.1126/science.274.5289.948 · Cited by 2,206 · see citing works
The p53 pathway: positive and negative feedback loops
Harris, S. L., & Levine, A. J. (2005) · Oncogene · doi:10.1038/sj.onc.1208615 · Cited by 1,967 · see citing works
A Medicinal Chemist’s Guide to Molecular Interactions
Bissantz, C., Kuhn, B., & Ståhl, M. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm100112j · Cited by 1,773 · see citing works
Regulating the p53 pathway: in vitro hypotheses, in vivo veritas
Toledo, F., & Wahl, G. M. (2006) · Nature reviews. Cancer · doi:10.1038/nrc2012 · Cited by 1,286 · see citing works
Awakening guardian angels: drugging the p53 pathway
Brown, C. J., Lain, S., Verma, C. S., Fersht, A. R., & Lane, D. P. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2763 · Cited by 881 · see citing works
Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy
Tovar, C., Rosinski, J., Filipovic, Z., Higgins, B., Kolinsky, K., Hilton, H., Zhao, X., Vu, B. T., Qing, W., Packman, K., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507493103 · Cited by 708 · see citing works
Self-citationShangary, S., Qin, D., McEachern, D., Liu, M., Miller, R. S., Qiu, S., Nikolovska-Coleska, Z., Ding, K., Wang, G., Chen, J., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0708917105 · Cited by 660 · see citing works
MDM2 inhibitors for cancer therapy
Vassilev, L. T. (2007) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2006.11.002 · Cited by 532 · see citing works
Self-citationThe p53 orchestra: Mdm2 and Mdmx set the tone
Wade, M., Wang, Y. V., & Wahl, G. M. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.01.009 · Cited by 450 · see citing works
Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX
Pazgier, M., Liu, M., Zou, G., Yuan, W., Li, C., Li, C., Li, J., Monbo, J., Zella, D., Tarasov, S. G., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900947106 · Cited by 391 · see citing works
Mdm2-mediated ubiquitylation: p53 and beyond
Marine, J.-C., & Lozano, G. (2010) · Cell Death & Differentiation · doi:10.1038/cdd.2009.68 · Cited by 354 · see citing works
Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4
Marine, J.-C., Francoz, S., Maetens, M., Wahl, G., Toledo, F., & Lozano, G. (2006) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401912 · Cited by 352 · see citing works
Danovi, D., Meulmeester, E., Pasini, D., Migliorini, D., Capra, M., Frenk, R., de Graaf, P., Francoz, S., Gasparini, P., Gobbi, A., et al. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.13.5835-5843.2004 · Cited by 310 · see citing works
Linke, K., Mace, P. D., Smith, C. A., Vaux, D. L., Silke, J., & Day, C. L. (2008) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4402309 · Cited by 288 · see citing works
A Stapled p53 Helix Overcomes HDMX-Mediated Suppression of p53
Bernal, F., Wade, M. R., Godes, M., Davis, T. N., Whitehead, D. G., Kung, A. L., Wahl, G. M., & Walensky, L. D. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.10.024 · Cited by 284 · see citing works
MDM2 promotes ubiquitination and degradation of MDMX
Pan, Y., & Chen, J. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.15.5113-5121.2003 · Cited by 246 · see citing works
Identification and Characterization of the First Small Molecule Inhibitor of MDMX
Reed, D., Shen, Y., Shelat, A. A., Arnold, L. A., Ferreira, A. M., Zhu, F., Mills, N., Smithson, D. C., Regni, C. A., Bashford, D., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.056747 · Cited by 198 · cited 2× · see citing works
“Efforts to identify MDMXspecific inhibitors have recently yielded a class of small molecules with in vitro binding activity in the high nanomolar range but relatively poor cellular potency and uncertain mechanism of cellular activity (29).”
BackgroundStructure of the human Mdmx protein bound to the p53 tumor suppressor transactivation domain
Popowicz, G. M., Czarna, A., & Holak, T. A. (2008) · Cell Cycle · doi:10.4161/cc.6365 · Cited by 195 · see citing works
The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo
Huang, L., Yan, Z., Liao, X., Li, Y., Yang, J., Wang, Z.-G., Zuo, Y., Kawai, H., Shadfan, M., Ganapathy, S., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102309108 · Cited by 193 · see citing works
Levels of HdmX expression dictate the sensitivity of normal and transformed cells to Nutlin-3
Patton, J. T., Mayo, L. D., Singhi, A. D., Gudkov, A. V., Stark, G. R., & Jackson, M. W. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3832 · Cited by 189 · see citing works
Mdmx as an essential regulator of p53 activity
Marine, J., & Jochemsen, A. G. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.03.151 · Cited by 186 · see citing works
Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction
Yu, S., Qin, D., Shangary, S., Chen, J., Wang, G., Ding, K., McEachern, D., Qiu, S., Nikolovska-Coleska, Z., Miller, R., et al. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm901400z · Cited by 180 · see citing works
p53 Activation by Small Molecules: Application in Oncology
Vassilev, L. T. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm058174k · Cited by 172 · see citing works
Self-citationTargeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry?
Wade, M., & Wahl, G. M. (2009) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-08-0423 · Cited by 170 · see citing works
Koblish, H. K., Zhao, S., Franks, C. F., Donatelli, R. R., Tominovich, R. M., LaFrance, L. V., Leonard, K. A., Gushue, J. M., Parks, D. J., Calvo, R. R., et al. (2006) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-05-0199 · Cited by 164 · see citing works
DNA damage-induced MDMX degradation is mediated by MDM2
Kawai, H., Wiederschain, D., Kitao, H., Stuart, J., Tsai, K. K. C., & Yuan, Z.-M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m308295200 · Cited by 163 · cited 1× · see citing works
“On the other hand, MDM2 can also ubiquitinate MDMX and is, therefore, responsible for its stability as well (11, 12).”
BackgroundHdmx modulates the outcome of p53 activation in human tumor cells
Wade, M., Wong, E. T., Tang, M., Stommel, J. M., & Wahl, G. M. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605405200 · Cited by 163 · see citing works
RING Domain–Mediated Interaction Is a Requirement for MDM2's E3 Ligase Activity
Kawai, H., Lopez-Pajares, V., Kim, M. M., Wiederschain, D., & Yuan, Z.-M. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1313 · Cited by 156 · see citing works
Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2
de Graaf, P., Little, N. A., Ramos, Y. F. M., Meulmeester, E., Letteboer, S. J. F., & Jochemsen, A. G. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213034200 · Cited by 143 · cited 1× · see citing works
“However, MDMX can enhance ligase activity of MDM2 toward p53 by forming MDM2/MDMX heterodimers (7, 8).”
BackgroundMolecular Basis for the Inhibition of p53 by Mdmx
Popowicz, G. M., Czarna, A., Rothweiler, U., Szwagierczak, A., Krajewski, M., Weber, L., & Holak, T. A. (2007) · Cell Cycle · doi:10.4161/cc.6.19.4740 · Cited by 131 · see citing works
MdmX Protein Is Essential for Mdm2 Protein-mediated p53 Polyubiquitination
Wang, X., Wang, J., & Jiang, X. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.213868 · Cited by 115 · see citing works
Xia, M., Knezevic, D., Tovar, C., Huang, B., Heimbrook, D. C., & Vassilev, L. T. (2008) · Cell Cycle · doi:10.4161/cc.7.11.5929 · Cited by 75 · see citing works
Self-citationKallen, J. A., Goepfert, A., Blechschmidt, A., Izaac, A., Geiser, M., Tavares, G., Ramage, P., Furet, P., Masuya, K., & Lisztwan, J. H. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m809096200 · Cited by 72 · see citing works
Role of Mdm4 in drug sensitivity of breast cancer cells
Lam, S., Lodder, K., Teunisse, A. F. A. S., Rabelink, M. J. W. E., Schutte, M., & Jochemsen, A. G. (2010) · Oncogene · doi:10.1038/onc.2009.522 · Cited by 52 · see citing works
Functions of MDMX in the Modulation of the p53‐Response
Lenos, K., & Jochemsen, A. G. (2011) · BioMed Research International · doi:10.1155/2011/876173 · Cited by 38 · see citing works
Inhibitors of MDM2 and MDMX: A Structural Perspective
Riedinger, C., & McDonnell, J. M. (2009) · Future Medicinal Chemistry · doi:10.4155/fmc.09.75 · Cited by 32 · see citing works
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Wade, M., Li, Y.-C., & Wahl, G. M. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3430 · Cited by 1,279 · see citing works
Modulators of Protein–Protein Interactions
Milroy, L.-G., Grossmann, T. N., Hennig, S., Brunsveld, L., & Ottmann, C. (2014) · Chemical Reviews · doi:10.1021/cr400698c · Cited by 497 · see citing works
Biologically informed deep neural network for prostate cancer discovery
Elmarakeby, H. A., Hwang, J., Arafeh, R., Crowdis, J., Gang, S., Liu, D., AlDubayan, S. H., Salari, K., Kregel, S., Richter, C., et al. (2021) · Nature · doi:10.1038/s41586-021-03922-4 · Cited by 456 · see citing works
Zhu, H., Gao, H., Ji, Y., Zhou, Q., Du, Z., Tian, L., Jiang, Y., Yao, K., & Zhou, Z. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01314-3 · Cited by 223 · see citing works
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Modell, A. E., Blosser, S. L., & Arora, P. S. (2016) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.05.008 · Cited by 184 · see citing works
Chasing molecular glue degraders: screening approaches
Domostegui, A., Nieto-Barrado, L., Perez-Lopez, C., & Mayor-Ruiz, C. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00197g · Cited by 200 · see citing works
The role of ubiquitin modification in the regulation of p53
Hock, A. K., & Vousden, K. H. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.05.022 · Cited by 168 · see citing works
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- Authors
- Graves, B., Thompson, T., Xia, M., Janson, C., Lukacs, C., Deo, D., Di Lello, P., Fry, D., Garvie, C., Huang, K.-S., Gao, L., Tovar, C., Lovey, A., Wanner, J., & Vassilev, L. T.
- Affiliations
- F. Hoffmann-La Roche AG (CH)
- Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-06-28
- Volume
- 109
- Issue
- 29
- Pages
- 11788-11793
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3406834
- OpenAlex
- W2128240743
- Cited by
- 230
- References
- 38
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 16 · 2023: 14 · 2022: 13 · 2021: 16 · 2020: 12 · 2019: 15 · 2018: 12 · 2017: 17 · 2016: 21 · 2015: 29 · 2014: 25 · 2013: 20 · 2012: 3
- FWCI
- 12.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- p53 activation, MDM2, MDMX, protein dimerization, small molecule inhibitors, p53 stabilization, cell cycle arrest, apoptosis, cancer therapy
- MeSH terms
- Crystallization, Humans, Hydantoins, Models, Molecular, Nuclear Proteins, Proto-Oncogene Proteins, Tetrazolium Salts, Thiazoles, Blotting, Western, Signal Transduction, Tumor Suppressor Protein p53, Apoptosis, Cell Cycle Proteins, Dimerization, Nuclear Magnetic Resonance, Biomolecular, Fluorescence Resonance Energy Transfer, Cell Line, Tumor, Proto-Oncogene Proteins c-mdm2
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