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Identification and Characterization of the First Small Molecule Inhibitor of MDMX
Open accessAbstract
The p53 pathway is disrupted in virtually every human tumor. In approximately 50% of human cancers, the p53 gene is mutated, and in the remaining cancers, the pathway is dysregulated by genetic lesions in other genes that modulate the p53 pathway. One common mechanism for inactivation of the p53 pathway in tumors that express wild-type p53 is increased expression of MDM2 or MDMX. MDM2 and MDMX bind p53 and inhibit its function by distinct nonredundant mechanisms. Small molecule inhibitors and small peptides have been developed that bind MDM2 in the p53-binding pocket and displace the p53 protein, leading to p53-mediated cell cycle exit and apoptosis. To date, peptide inhibitors of MDMX have been developed, but no small molecule inhibitors have been reported. We have developed biochemical and cell-based assays for high throughput screening of chemical libraries to identify MDMX inhibitors and identified the first MDMX inhibitor SJ-172550. This compound binds reversibly to MDMX and effectively kills retinoblastoma cells in which the expression of MDMX is amplified. The effect of SJ-172550 is additive when combined with an MDM2 inhibitor. Results from a series of biochemical and structural modeling studies suggest that SJ-172550 binds the p53-binding pocket of MDMX, thereby displacing p53. This lead compound is a useful chemical scaffold for further optimization of MDMX inhibitors that may eventually be used to treat pediatric cancers and various adult tumors that overexpress MDMX or have similar genetic lesions. When combined with selective MDM2 inhibitors, SJ-172550 may also be useful for treating tumors that express wild-type p53.
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“The small molecule SJ-172550 was identified as an MDMX–p53-selective antagonist105 that exhibited additive cytotoxicity with nutlin 3a in MDMX-amplified retinoblastoma cells. However, subsequent analyses showed that SJ-172550 forms covalent adducts with cysteine residues in the p53-binding domain of both MDM2 and MDMX.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [105]
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“We used a cell-permeable and MDMx-specific inhibitor, SJ-172550, which binds to the p53-binding pocket at the N terminus of MDMx and blocks p53 docking (Reed et al., 2010).”
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“Furthermore, given that a MDMX knockout (MDMX -/-) mouse model has shown that restoration of wild-type p53 function leads to fewer haematological and gastrointestinal toxicities than the restoration of wild-type p53 function in an analogous MDM2 knockout (-/-) model [31], the pharmacological inhibition of HDMX with co…”
BackgroundSelf-citationAberrant activation of p53 due to loss of MDM2 or MDMX causes early lens dysmorphogenesis
Zhang, Y.-W., Zhang, X., & Lu, H. (2014) · Developmental Biology · doi:10.1016/j.ydbio.2014.09.017 · Cited by 10
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“Of the reported HDMX inhibitor molecules, SJ-172550 is not a competitive inhibitor and instead covalently modifies HDMX to induce a conformational change (Bista et al., 2012; Reed et al., 2010), CTX1 is an acridine-containing (and potential PAIN) compound with an unknown HDMX-inhibitory mechanism (Karan et al.”
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“In contrast, MDM4 (and mRNA in mouse fibroblast), p53, and acetylated p53 levels were not affected by SJ-172550 treatment (Figure S2B), suggesting that SJ-172550 might function as an MDM4 inhibitor in a cell type-specific manner.”
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MDM2/P53 Inhibitors as Sensitizing Agents for Cancer Chemotherapy
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Native PAGE to study the interaction between the oncosuppressor p53 and its protein ligands
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Targeting the MDM2–p53 Protein–Protein Interaction
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p53-Reactivating Molecules as Research Tools and Anticancer Drugs
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“The SJ-172550 drug binds primarily Hdm4 and, to a lesser effect, Hdm2 [36].”
BackgroundInhibition of the MDM2/p53 Interaction Design, Synthesis and Evaluation of MDM2 Inhibitors
Pettersson, M. (2015) · Gothenburg University Publications Electronic Archive (Gothenburg University) · Cited by 1
Upstream Targets in the p53 Pathway
McCarthy, A. R., & Laı́n, S. (2012) · Springer eBooks · doi:10.1007/978-1-4614-3676-8_12
The role of TRIM39 in cell cycle and apoptosis
Huang, N.-J. (2013) · DukeSpace (Duke University)
Protein–Protein Interactions as Drug Discovery Targets
Dömling, A. S. S. (2010) · Wiley eBooks · doi:10.1002/0471266949.bmc129
Small Molecules as Research Tools for Studying the Biology of the Tumour Suppressor p53
Spinnler, C. (2011) · Figshare
Touqan, N. (2014) · UPT. Syiah Kuala University Library (Syiah Kuala University)
Modulation of p53's transcriptional function by small molecules
Nikulenkov, F. (2011) · Figshare
Restoring p53 Function: Novel Anticancer Approaches for an Old Foe
(2012) · BENTHAM SCIENCE PUBLISHERS eBooks · doi:10.2174/9781608054787112010010
“A high resolution structure of MDM2 and MDMX bound to p53 has demonstrated that the p53-binding pocket for MDMX is smaller than that for MDM2, thereby suggesting a potential explanation for the lower affinity binding of NUTLIN-3 to MDMX compared with MDM2 [100].”
BackgroundMethodInduction of p53 Dependent Cellular Senescence Through HdmX Inhibition or YPEL3 Expression
Miller, K. L. (2010) · Journal of Bioresource Management
Preclinical Pharmacology of the MDM2 Antagonist Nutlin-3a
Zhang, F. (2011) · doi:10.21007/etd.cghs.2011.0372
“Other compounds such as MI-219 [16] (also known as AT219), nutlin-3a [17], SJ-172550 [18], and benzodiazepines [19] are in preclinical development stage.”
BackgroundMechanisms of p53-mediated Intrinsic and Extrinsic Tumor Suppression
Selivanova, G., Höglund, P., Piaggio, G., Elena, R., Pereira, T., Wright, A. R., Wadelius, C., & Universitit, U. (2014)
Development of a Mirror-Image Screening System for Chiral Natural Products
Noguchi, T. (2017) · Springer theses · doi:10.1007/978-981-10-6623-8_2
Molecular Designing of Small-Molecule Inhibitors for Apoptosis Regulation
Yoshimori, A., & Tanuma, S. (2017) · Current human cell research and applications · doi:10.1007/978-981-10-7296-3_10
Generation of reporter cell lines by genome editing to probe p53 activity
Tolay, N. (2018) · Sabanci University
Hit-to-lead optimization of pharmaceutical interesting tryptophanol-derived scaffolds
Barcherini, V. (2016) · Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT)
Kojima, K., & Andreeff, M. (2015) · Wiley eBooks · doi:10.1002/9781118468678.ch36
Data from A Small-Molecule Inhibitor of MDMX Activates p53 and Induces Apoptosis
Wang, H., Ma, X., Ren, S., Buolamwini, J. K., & Yan, C. (2023) · doi:10.1158/1535-7163.c.6531407
Data from Nutlin-3a Is a Potential Therapeutic for Ewing Sarcoma
Pishas, K. I., Al‐Ejeh, F., Zinonos, I., Kumar, R., Evdokiou, A., Brown, M. P., Callen, D. F., & Neilsen, P. M. (2023) · doi:10.1158/1078-0432.c.6519999.v1
Data from A Small-Molecule Inhibitor of MDMX Activates p53 and Induces Apoptosis
Wang, H., Ma, X., Ren, S., Buolamwini, J. K., & Yan, C. (2023) · doi:10.1158/1535-7163.c.6531407.v1
Data from Nutlin-3a Is a Potential Therapeutic for Ewing Sarcoma
Pishas, K. I., Al‐Ejeh, F., Zinonos, I., Kumar, R., Evdokiou, A., Brown, M. P., Callen, D. F., & Neilsen, P. M. (2023) · doi:10.1158/1078-0432.c.6519999
Hdm2 disrupts HdmX-mediated nuclear export of p53 by sequestering it in nucleus
Ni, Y., Chen, H., Cheng, X., Sun, B., Wu, Z., Zhan, Q., & Zhuang, Z. (2024) · Experimental Cell Research · doi:10.1016/j.yexcr.2024.114185
Protein-protein interaction inhibitors in cancer
Hardcastle, I. R., Goujon-Ricci, J., & Thompson, W. I. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-29808-0.00067-4
Recent advances in the understanding of TP53 in haematological malignancies
Ng, J. Y., & Talaulikar, D. (2026) · Pathology · doi:10.1016/j.pathol.2026.03.014
Development of a high-throughput assay format to identify inhibitors of HAX1–CLPB interaction
Fan, Y., Dahiya, V., Chatterjee, D., Fleck, M., Aretz, J., Nagel, F., Maskos, K., Makino, D. L., Noeske, J., Pangratz-Fuehrer, S., et al. (2026) · Results in Chemistry · doi:10.1016/j.rechem.2026.103765
Metadata
- Authors
- 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., Cicero, S. A., Schulman, B. A., Jochemsen, A. G., Guy, R. K., & Dyer, M. A.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Leiden University Medical Center (NL)
- Corresponding author
- Dyer, Michael A.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-04
- Volume
- 285
- Issue
- 14
- Pages
- 10786-10796
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2856285
- OpenAlex
- W1997557358
- Cited by
- 198
- References
- 39
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 6 · 2023: 8 · 2022: 8 · 2021: 5 · 2020: 6 · 2019: 10 · 2018: 10 · 2017: 14 · 2016: 19 · 2015: 9 · 2014: 25 · 2013: 20 · 2012: 15
- FWCI
- 11.37
- 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)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- International Retinal Research Foundation
- Research to Prevent Blindness
- Vanderbilt University
- American Lebanese Syrian Associated Charities
- National Institutes of Health
- National Eye Institute (R01EY014867)
- National Cancer Institute
- 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
- MDMX, small molecule inhibitors, p53 pathway, MDM2, retinoblastoma, MDM2 inhibitors, combination therapy, high-throughput screening, childhood cancer
- MeSH terms
- Acetates, Animals, Antineoplastic Agents, Computer Simulation, Humans, Pyrazoles, Retinoblastoma, Tumor Suppressor Protein p53, Apoptosis, Cell Line, Tumor, Mice, Proto-Oncogene Proteins c-mdm2, Small Molecule Libraries, High-Throughput Screening Assays
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