Discovery of Dual Inhibitors of MDM2 and XIAP for Cancer Treatment
Open accessAbstract
MDM2 and XIAP are mutually regulated. Binding of MDM2 RING protein to the IRES region on XIAP mRNA results in MDM2 protein stabilization and enhanced XIAP translation. In this study, we developed a protein-RNA fluorescence polarization (FP) assay for high-throughput screening (HTS) of chemical libraries. Our FP-HTS identified eight inhibitors that blocked the MDM2 protein-XIAP RNA interaction, leading to MDM2 degradation. The compound-induced MDM2 downregulation resulted not only in inhibition of XIAP expression, but also in activation of p53, which contributed to cancer cell apoptosis in vitro and inhibition of cancer cell proliferation in vivo. Importantly, one of the MDM2/XIAP inhibitors, MX69, showed minimal inhibitory effect on normal human hematopoiesis in vitro and was very well tolerated in animal models.
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?
The MDM2/XIAP dual-target inhibitor MX69 can simultaneously inhibit XIAP and activate p53 to exert anti-tumor activity.
“The MDM2/XIAP (X-linked inhibitor of apoptosis protein) dual-target inhibitor MX69 can simultaneously inhibit XIAP and activate p53 to exert anti-tumor activity.”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [117]
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
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
Mdm2 promotes the rapid degradation of p53
Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997) · Nature · doi:10.1038/387296a0 · Cited by 4,506 · see citing works
Momand, 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
MDM2, MDMX and p53 in oncogenesis and cancer therapy
Wade, M., Li, Y.-C., & Wahl, G. M. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3430 · Cited by 1,279 · cited 2× · see citing works
“Efforts have beenmade to target the XIAP-caspase andMDM2-p53 interactions or MDM2 E3 ligase activity as therapeutic strategies (Huang et al., 2004; Rajapakse, 2007; RayCoquard et al., 2012; Shangary et al., 2008; Vassilev et al., 2004; Wade et al., 2013; Yang et al., 2005).”
MethodThe MDM2 gene amplification database
Momand, J. (1998) · Nucleic Acids Research · doi:10.1093/nar/26.15.3453 · Cited by 982 · see citing works
Shangary, 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
Ray-Coquard, I., Blay, J.-Y., Italiano, A., Le Cesne, A., Penel, N., Zhi, J., Heil, F., Rueger, R., Graves, B., Ding, M., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70474-6 · Cited by 571 · see citing works
Inhibitor of Apoptosis Proteins: Translating Basic Knowledge into Clinical Practice
Schimmer, A. D. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1918 · Cited by 513 · see citing works
Juven‐Gershon, T., Barak, Y., Zauberman, A., George, D. L., & Oren, M. (1993) · PubMed · Cited by 332 · see citing works
Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells
Yang, Y., Ludwig, R. L., Jensen, J. P., Pierre, S. A., Medaglia, M. V., Davydov, I. V., Safiran, Y. J., Oberoi, P., Kenten, J. H., Phillips, A. C., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.04.029 · Cited by 321 · see citing works
A new internal-ribosome-entry-site motif potentiates XIAP- mediated cytoprotection
Holčı́k, M., Lefebvre, C. A., Yeh, C., Chow, T. Y.-K., & Korneluk, R. G. (1999) · Nature Cell Biology · doi:10.1038/11109 · Cited by 302 · see citing works
The human MDM-2 oncogene is overexpressed in leukemias
Bueso-Ramos, C., Yang, Y. S., deLeon, E., McCown, P., Stass, S. A., & Albitar, M. X. (1993) · Blood · doi:10.1182/blood.v82.9.2617.bloodjournal8292617 · Cited by 292 · see citing works
Li, M., Zhang, Z., Hill, D. L., Wang, H., & Zhang, R. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-3066 · Cited by 273 · 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 · cited 2× · see citing works
“Ubiquitination Assay The ubiquitination assay was performed as described previously (Pan and Chen, 2003).”
Methodp53 mRNA controls p53 activity by managing Mdm2 functions
Candeias, M. M., Malbert-Colas, L., Powell, D. J., Daskalogianni, C., Maslon, M. M., Naski, N., Bourougaa, K., Calvo, F. M., & Fåhræus, R. (2008) · Nature Cell Biology · doi:10.1038/ncb1770 · Cited by 241 · see citing works
Berezovskaya, O., Schimmer, A. D., Glinskii, A. B., Pinilla, C., Hoffman, R. M., Reed, J. C., & Glinsky, G. V. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-2649 · Cited by 227 · see citing works
Regulation of XIAP Translation and Induction by MDM2 following Irradiation
Gu, L., Zhu, N., Zhang, H., Durden, D. L., Feng, Y., & Zhou, M. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.03.002 · Cited by 178 · see citing works
Self-citationTamm, I., Richter, S., Oltersdorf, D., et al. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-03-0642 · Cited by 166 · see citing works
Zhang, X., Gu, L., Li, J., Shah, N., He, J., Yang, L., Hu, Q., & Zhou, M. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1546 · Cited by 130 · see citing works
Self-citationOverexpression of XIAP expression in renal cell carcinoma predicts a worse prognosis
Mizutani, Y., Nakanishi, H., Li, Y. Z., Matsubara, H., Yamamoto, K., Sato, N., Shiraishi, T., Nakamura, T., Mikami, K., Okihara, K., et al. (2007) · International Journal of Oncology · doi:10.3892/ijo.30.4.919 · Cited by 129 · see citing works
Zhou, M., Yeager, A., Smith, S. D., & Findley, H. W. (1995) · Blood · doi:10.1182/blood.v85.6.1608.bloodjournal8561608 · Cited by 129 · see citing works
Self-citationMolecular and biochemical pharmacology of mitoxantrone
Durr, F. E., Wallace, R. E., & Citarella, R. V. (1983) · Cancer Treatment Reviews · doi:10.1016/0305-7372(83)90016-6 · Cited by 128 · see citing works
Nakayama, T., Toguchida, J., Wadayama, B., Kanoe, H., Kotoura, Y., & Sasaki, M. S. (1995) · International Journal of Cancer · doi:10.1002/ijc.2910640511 · Cited by 122 · see citing works
The pyrido[b]indole MDM2 inhibitor SP-141 exerts potent therapeutic effects in breast cancer models
Wang, W., Qin, J., Voruganti, S., Srivenugopal, K. S., Nag, S. A., Patil, S. A., Sharma, H., Wang, M., Wang, H., Buolamwini, J. K., et al. (2014) · Nature Communications · doi:10.1038/ncomms6086 · Cited by 99 · see citing works
Zheng, S., Chen, Y., Donahue, C. P., Wolfe, M. S., & Varani, G. (2009) · Chemistry & Biology · doi:10.1016/j.chembiol.2009.03.009 · Cited by 98 · see citing works
MDM2 Protein Overexpression Promotes Proliferation and Survival of Multiple Myeloma Cells
Teoh, G. K. H., Urashima, M., Ogata, A., Chauhan, D., DeCaprio, J. A., Treon, S. P., Schlossman, R. L., & Anderson, K. C. (1997) · Blood · doi:10.1182/blood.v90.5.1982 · Cited by 97 · see citing works
MDM2 Regulates Vascular Endothelial Growth Factor mRNA Stabilization in Hypoxia
Zhou, S., Gu, L., He, J., Zhang, H., & Zhou, M. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.06085-11 · Cited by 95 · see citing works
Self-citationActivation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis
Iancu-Rubin, C., Mosoyan, G., Glenn, K., Gordon, R. E., Nichols, G. L., & Hoffman, R. (2014) · Experimental Hematology · doi:10.1016/j.exphem.2013.11.012 · Cited by 90 · see citing works
Zhou, M., Gu, L., Abshire, T. C., Homans, A., Billett, A. L., Yeager, A., & Findley, H. W. (2000) · Leukemia · doi:10.1038/sj.leu.2401619 · Cited by 88 · see citing works
Self-citationHDM2 Protein Overexpression and Prognosis in Primary Malignant Melanoma
Polsky, D. (2002) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/94.23.1803 · Cited by 82 · see citing works
MDM2 regulates MYCN mRNA stabilization and translation in human neuroblastoma cells
Gu, L., Zhang, H., He, J., Li, J., Huang, M. J., & Zhou, M. (2011) · Oncogene · doi:10.1038/onc.2011.343 · Cited by 73 · see citing works
Self-citationCarter, B. Z., Mak, D. H. F., Schober, W. D., Koller, E., Pinilla, C., Vassilev, L. T., Reed, J. C., & Andreeff, M. (2009) · Blood · doi:10.1182/blood-2009-03-212563 · Cited by 67 · see citing works
Huang, M. J., Zhang, H., Liu, T., Tian, D., Gu, L., & Zhou, M. (2012) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-12-0425 · Cited by 67 · see citing works
Self-citationNatural Product MDM2 Inhibitors: Anticancer Activity and Mechanisms of Action
Qin, J., Nag, S. A., Voruganti, S., Wang, W., & Zhang, R. (2012) · Current Medicinal Chemistry · doi:10.2174/092986712803988910 · Cited by 57 · see citing works
Lewis, S. M., & Holčı́k, M. (2005) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401602 · Cited by 54 · see citing works
Antagonizing XIAP-mediated caspase-3 inhibition
Huang, Y., Lu, M., & Wu, H. (2004) · Cancer Cell · doi:10.1016/s1535-6108(03)00340-4 · Cited by 50 · see citing works
High-Throughput Screening Fluorescence Polarization Assay for Tumor-Specific Hsp90
Du, Y., Moulick, K., Rodina, A., et al. (2007) · SLAS DISCOVERY · doi:10.1177/1087057107306067 · Cited by 47 · see citing works
Self-citationHe, J., Gu, L., Zhang, H., et al. (2011) · Cell Cycle · doi:10.4161/cc.10.17.17118 · Cited by 46 · see citing works
Self-citationTriptolide induces apoptosis of gastric cancer cells via inhibiting the overexpression of MDM2
Wang, B.-Y., Cao, J., Chen, J., & Liu, Q. (2014) · Medical Oncology · doi:10.1007/s12032-014-0270-7 · Cited by 40 · see citing works
Mdm2 increases cellular invasiveness by binding to and stabilizing the Slug mRNA
Jung, C., Kim, J., Park, J. K., Hwang, S., Moon, S., Kim, W., & Um, H. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.02.035 · Cited by 38 · see citing works
Riahi, S., Ganjali, M. R., Dinarvand, R., et al. (2008) · Chemical Biology & Drug Design · doi:10.1111/j.1747-0285.2008.00653.x · Cited by 35 · see citing works
Inhibition of MDM2 homodimerization by XIAP IRES stabilizes MDM2, influencing cancer cell survival
Liu, T., Zhang, H., Xiong, J., Yi, S., Gu, L., & Zhou, M. (2015) · Molecular Cancer · doi:10.1186/s12943-015-0334-0 · Cited by 26 · see citing works
Self-citationSmall Molecule Inhibitors of the XIAP Protein-Protein Interaction
Rajapakse, H. A. (2007) · Current Topics in Medicinal Chemistry · doi:10.2174/156802607780906816 · Cited by 20 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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
MDM2/X inhibitors as radiosensitizers for glioblastoma targeted therapy
Miles, X., Vandevoorde, C., Hunter, A., & Bolcaen, J. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.703442 · Cited by 40 · see citing works
- Authors
- Gu, L., Zhang, H., Liu, T., Zhou, S., Du, Y., Xiong, J., Yi, S., Qu, C.-K., Fu, H., & Zhou, M.
- Affiliations
- Emory University (US)
- Tongji Hospital (CN)
- Corresponding author
- Zhou, Muxiang
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 30
- Issue
- 4
- Pages
- 623-636
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC5079537
- OpenAlex
- W2522678060
- Cited by
- 86
- References
- 43
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 8 · 2023: 5 · 2022: 7 · 2021: 12 · 2020: 10 · 2019: 14 · 2018: 12 · 2017: 9 · 2016: 1
- FWCI
- 6.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- R01 (CA180519, CA123490, CA143107)
- Hyundai Hope On Wheels (79387GA)
- St. Baldrick’s Foundation (422224)
- CURE Childhood Cancer
- U01 (CA168449)
- National Natural Science Foundation of China (81472488)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- MDM2, XIAP, dual inhibitors, high-throughput screening, MDM2 degradation, p53 activation, apoptosis, tumor cell proliferation, cancer therapy
- MeSH terms
- Animals, Female, Humans, Mice, SCID, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, X-Linked Inhibitor of Apoptosis Protein, Proto-Oncogene Proteins c-mdm2, Precursor Cell Lymphoblastic Leukemia-Lymphoma
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
