Small-Molecule Ligands of Methyl-Lysine Binding Proteins

被引：88

作者：

Herold, J. Martin ^{[1
]}

Wigle, Tim J. ^{[1
]}

Norris, Jacqueline L. ^{[1
]}

Lam, Robert ^{[2
]}

Korboukh, Victoria K. ^{[1
]}

Gao, Cen ^{[1
]}

Ingerman, Lindsey A. ^{[1
]}

Kireev, Dmitri B. ^{[1
]}

Senisterra, Guillermo ^{[2
]}

Vedadi, Masoud ^{[2
]}

Tripathy, Ashutosh ^{[3
]}

Brown, Peter J. ^{[2
]}

Arrowsmith, Cheryl H. ^{[2
]}

Jin, Jian ^{[1
]}

Janzen, William P. ^{[1
]}

Frye, Stephen V. ^{[1
]}

机构：

[1] Univ N Carolina, Div Med Chem & Nat Prod, UNC Eshelman Sch Pharm, Ctr Integrated Chem Biol & Drug Discovery, Chapel Hill, NC 27599 USA

[2] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada

[3] Univ N Carolina, Dept Biochem & Biophys, UNC Macromol Interact Facil, Chapel Hill, NC 27599 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 07期

基金：

加拿大创新基金会; 英国惠康基金;

关键词：

HISTONE H3; TRANSCRIPTIONAL REPRESSOR; L3MBTL1; RECOGNITION; ANTAGONISTS; INHIBITORS; PROMOTES; TAIL;

D O I：

10.1021/jm200045v

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Proteins which bind methylated lysines ("readers" of the histone code) are important components in the epigenetic regulation of gene expression and can also modulate other proteins that contain methyl-lysine such as p53 and Rb. Recognition of methyl-lysine marks by MBT domains leads to compaction of chromatin and a repressed transcriptional state. Antagonists of MBT domains would serve as probes to interrogate the functional role of these proteins and initiate the chemical biology of methyl-lysine readers as a target class. Small-molecule MBT antagonists were designed based on the structure of histone peptide - MBT complexes and their interaction with MBT domains determined using a chemiluminescent assay and ITC. The ligands discovered antagonize native histone peptide binding, exhibiting 5-fold stronger binding affinity to L3MBTL1 than its preferred histone peptide. The first cocrystal structure of a small molecule bound to L3MBTL1 was determined and provides new insights into binding requirements for further ligand design.

引用

页码：2504 / 2511

页数：8

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