On the Mechanism of Action of SJ-172550 in Inhibiting the Interaction of MDM4 and p53
Open accessAbstract
SJ-172550 (1) was previously discovered in a biochemical high throughput screen for inhibitors of the interaction of MDMX and p53 and characterized as a reversible inhibitor (J. Biol. Chem. 2010; 285:10786). Further study of the biochemical mode of action of 1 has shown that it acts through a complicated mechanism in which the compound forms a covalent but reversible complex with MDMX and locks MDMX into a conformation that is unable to bind p53. The relative stability of this complex is influenced by many factors including the reducing potential of the media, the presence of aggregates, and other factors that influence the conformational stability of the protein. This complex mechanism of action hinders the further development of compound 1 as a selective MDMX inhibitor.
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Achiral oxoapomorphine served as reactive species to form covalent bond at Cys77 of MDM2 with Michael acceptors, leading to inhibition of binding to p53.
“Among these, the achiral oxoapomorphine, which was converted from chiral apomorphine under aerobic conditions, served as the reactive species to form a covalent bond at Cys77 of MDM2 with Michael acceptors, leading to the inhibitory effect against the binding to p53.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [219]
The small molecule SJ-172550 was identified as an MDMX-p53-selective antagonist, but subsequent analyses showed that it forms covalent adducts with cysteine residues in the p53-binding domain of both MDM2 and MDMX.
“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 [106]
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- Authors
- Bista, M., Smithson, D., Pecak, A., Salinas, G., Pustelny, K., Min, J., Pirog, A., Finch, K., Zdzalik, M., Waddell, B., Wladyka, B., Kedracka-Krok, S., Dyer, M. A., Dubin, G., & Guy, R. K.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Jagiellonian University (PL)
- Corresponding author
- Guy, R. Kiplin
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-06-04
- Volume
- 7
- Issue
- 6
- Pages
- e37518
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3366986
- OpenAlex
- W2081465242
- Cited by
- 58
- References
- 24
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 2 · 2021: 4 · 2020: 4 · 2019: 6 · 2018: 5 · 2017: 5 · 2016: 9 · 2015: 3 · 2014: 4 · 2013: 7 · 2012: 2
- FWCI
- 2.53
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Homo Politicus (Academy of Humanities and Economics in Lodz) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- American Lebanese Syrian Associated Charities
- European Commission (POIG.02.01.00-12-167/08, POIG.02.01.00-12-064/08)
- 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 › Ubiquitin and proteasome pathways
- Keywords
- MDM4, p53, MDMX, protein-protein interaction inhibition, reversible inhibitors, protein conformational stability, reducing power, drug development
- MeSH terms
- Acetates, Amino Acid Sequence, Buffers, Humans, Models, Biological, Molecular Sequence Data, Nuclear Proteins, Peptides, Protein Binding, Protein Conformation, Proto-Oncogene Proteins, Pyrazoles, Temperature, Tumor Suppressor Protein p53, Pliability, Cell Cycle Proteins, Inhibitory Concentration 50, Protein Stability
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