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

被引：45

作者：

Bista, Michal ^{[1
,2
]}

Smithson, David ^{[3
]}

Pecak, Aleksandra ^{[2
]}

Salinas, Gabriella ^{[3
]}

Pustelny, Katarzyna ^{[2
]}

Min, Jaeki ^{[3
]}

Pirog, Artur ^{[4
]}

Finch, Kristin ^{[3
,5
]}

Zdzalik, Michal ^{[6
]}

Waddell, Brett ^{[7
]}

Wladyka, Benedykt ^{[2
]}

Kedracka-Krok, Sylwia ^{[4
,8
]}

Dyer, Michael A. ^{[5
,9
,10
]}

Dubin, Grzegorz ^{[6
,8
]}

Guy, R. Kiplin ^{[3
]}

机构：

[1] Max Planck Inst Biochem, D-82152 Martinsried, Germany

[2] Jagiellonian Univ, Dept Analyt Biochem, Fac Biochem Biophys & Biotechnol, Krakow, Poland

[3] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, Memphis, TN 38105 USA

[4] Jagiellonian Univ, Fac Biochem Biophys & Biotechnol, Dept Phys Biochem, Krakow, Poland

[5] St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA

[6] Jagiellonian Univ, Fac Biochem Biophys & Biotechnol, Dept Microbiol, Krakow, Poland

[7] St Jude Childrens Res Hosp, Hartwell Ctr Biotechnol, Memphis, TN 38105 USA

[8] Malopolska Ctr Biotechnol, Krakow, Poland

[9] Univ Tennessee, Hlth Sci Ctr, Dept Ophthalmol, Memphis, TN USA

[10] Howard Hughes Med Inst, Chevy Chase, MD USA

来源：

PLOS ONE | 2012年 / 7卷 / 06期

关键词：

MOLECULE; RECEPTOR; LIGANDS; PATHWAY;

D O I：

10.1371/journal.pone.0037518

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：9

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