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

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 MA, Dubin G, Guy RK - PLoS ONE (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Max-Planck Institute for Biochemistry, Martinsried, Germany.

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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Structures of relevant compounds.Panel A. Structure of SJ-172550 (1) and a non-reactive analog (2). Panel B. The potential mechanism of covalent adduct formation.
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pone-0037518-g001: Structures of relevant compounds.Panel A. Structure of SJ-172550 (1) and a non-reactive analog (2). Panel B. The potential mechanism of covalent adduct formation.

Mentions: More recently, small molecule inhibitors of MDMX have been described. The first (Figure 1, Panel A, SJ-172550, 1) was identified in a high-throughput screen using a biochemical assay to recapitulate the binding of MDMX and p53 [10]. SJ-172550 could compete for the wild type p53 peptide binding to MDMX with an EC50 ∼ 5 µM and caused p53 dependent cell death of retinoblastoma cells [10]. For comparison, nutlin-3a inhibited the MDMX-p53 interaction with an EC50 ∼ 30 µM [10]. Another small molecule inhibitor of MDMX-p53 that has been characterized is WK298 [11]. This molecule binds to MDMX with a binding constant of ∼ 20 µM and structural studies have shown that it mimics binding of the p53 peptide [11]. In addition to small molecule inhibitors of the MDMX-p53 interaction, there have been several reports of peptide inhibitors [12]. For example, a stapled peptide that mimics the p53 helix that interacts with the MDMX protein was effective at disrupting the MDMX-p53 interaction in vitro and in vivo[13].


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

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 MA, Dubin G, Guy RK - PLoS ONE (2012)

Structures of relevant compounds.Panel A. Structure of SJ-172550 (1) and a non-reactive analog (2). Panel B. The potential mechanism of covalent adduct formation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3366986&req=5

pone-0037518-g001: Structures of relevant compounds.Panel A. Structure of SJ-172550 (1) and a non-reactive analog (2). Panel B. The potential mechanism of covalent adduct formation.
Mentions: More recently, small molecule inhibitors of MDMX have been described. The first (Figure 1, Panel A, SJ-172550, 1) was identified in a high-throughput screen using a biochemical assay to recapitulate the binding of MDMX and p53 [10]. SJ-172550 could compete for the wild type p53 peptide binding to MDMX with an EC50 ∼ 5 µM and caused p53 dependent cell death of retinoblastoma cells [10]. For comparison, nutlin-3a inhibited the MDMX-p53 interaction with an EC50 ∼ 30 µM [10]. Another small molecule inhibitor of MDMX-p53 that has been characterized is WK298 [11]. This molecule binds to MDMX with a binding constant of ∼ 20 µM and structural studies have shown that it mimics binding of the p53 peptide [11]. In addition to small molecule inhibitors of the MDMX-p53 interaction, there have been several reports of peptide inhibitors [12]. For example, a stapled peptide that mimics the p53 helix that interacts with the MDMX protein was effective at disrupting the MDMX-p53 interaction in vitro and in vivo[13].

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Max-Planck Institute for Biochemistry, Martinsried, Germany.

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.

Show MeSH