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Public Library of Science, PLoS ONE, 6(7), p. e37518, 2012

DOI: 10.1371/journal.pone.0037518

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On the Mechanism of Action of SJ-172550 in Inhibiting the Interaction of MDM4 and p53

Journal article published in 2012 by Michal Bista, David Smithson, Aleksandra Pecak, Gabriella Salinas, Katarzyna Pustelny, Jaeki Min, Artur Pirog, Kristin Finch, Michal Zdzalik, Brett Waddell, Benedykt Wladyka, Sylwia Kedracka-Krok, Michael A. Dyer, Grzegorz Dubin, R. Kiplin Guy ORCID and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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.