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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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Self-citationMDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy
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Research works printed but not linked: 2
- Dang, 2002, Cancer Res., 62, 1222
- Anderson, 2007, Int. J. Oncol., 31, 545
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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
Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting
Borrero, L. J. H., & El‐Deiry, W. S. (2021) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2021.188556 · Cited by 805
Drugging the p53 pathway: understanding the route to clinical efficacy
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“Alternatively, small molecules that would act synergistically with nutlin-like compounds (that act only on MDM2) by independently inhibiting MDM4 have been very recently discovered ( Figure 5d )”
Background
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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