On the mechanism of action of SJ-172550 in inhibiting the interaction of MDM4 and p53

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 compli...

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Bibliographic Details
Published in:PloS one 2012-06, Vol.7 (6), p.e37518
Main Authors: Bista, Michal, Smithson, David, Pecak, Aleksandra, Salinas, Gabriella, Pustelny, Katarzyna, Min, Jaeki, Pirog, Artur, Finch, Kristin, Zdzalik, Michal, Waddell, Brett, Wladyka, Benedykt, Kedracka-Krok, Sylwia, Dyer, Michael A, Dubin, Grzegorz, Guy, R Kiplin
Format: Article
Language:English
Subjects:
Acetates - chemistry
Acetates - pharmacology
Amino Acid Sequence
Apoptosis
Biochemistry
Biology
Biophysics
Biotechnology
Breast cancer
Buffers
Chemistry
Coordination compounds
Enzyme inhibitors
Humans
Inhibitors
Inhibitory Concentration 50
Kinases
Ligands
Locks
Mass spectrometry
Mode of action
Models, Biological
Molecular Sequence Data
Neurobiology
Neurosciences
Nuclear Proteins - chemistry
Nuclear Proteins - metabolism
p53 Protein
Peptides
Peptides - metabolism
Pharmaceutical sciences
Pliability - drug effects
Protein Binding - drug effects
Protein Conformation
Protein Stability - drug effects
Proteins
Proto-Oncogene Proteins - chemistry
Proto-Oncogene Proteins - metabolism
Pyrazoles - chemistry
Pyrazoles - pharmacology
Scientific imaging
Stability
Temperature
Thyroid gland
Tumor proteins
Tumor Suppressor Protein p53 - chemistry
Tumor Suppressor Protein p53 - metabolism
Tumors
Citations: Items that this one cites
Items that cite this one
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0037518