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

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

doi:10.1371/journal.pone.0037518

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

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

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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.

Original language	English
Article number	e37518
Journal	PLoS ONE
Volume	7
Issue number	6
DOIs	https://doi.org/10.1371/journal.pone.0037518
State	Published - Jun 4 2012

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title = "On the mechanism of action of SJ-172550 in inhibiting the interaction of MDM4 and p53",

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.",

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AU - Bista, Michal

AU - Smithson, David

AU - Pecak, Aleksandra

AU - Salinas, Gabriella

AU - Pustelny, Katarzyna

AU - Min, Jaeki

AU - Pirog, Artur

AU - Finch, Kristin

AU - Zdzalik, Michal

AU - Waddell, Brett

AU - Wladyka, Benedykt

AU - Kedracka-Krok, Sylwia

AU - Dyer, Michael A.

AU - Dubin, Grzegorz

AU - Guy, R. Kiplin

PY - 2012/6/4

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

Abstract

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