New Potent Bisubstrate Inhibitors of Histone Acetyltransferase p300: Design, Synthesis and Biological Evaluation

被引：16

作者：

Kwie, Franciane Ho A. ^{[1
,2
]}

Briet, Martine ^{[2
,3
]}

Soupaya, David ^{[1
,2
]}

Hoffmann, Pascal ^{[1
,2
]}

Maturano, Marie ^{[1
,2
]}

Rodriguez, Frederic ^{[1
,2
]}

Blonski, Casimir ^{[1
,2
]}

Lherbet, Christian ^{[1
,2
]}

Baudoin-Dehoux, Cecile ^{[1
,2
]}

机构：

[1] CNRS, UMR 5068, SPCMIB, Lab Synth & Phys Chim Mol Interet Biol, F-31062 Toulouse 9, France

[2] Univ Toulouse, SPCMIB, UPS, Lab Synth & Phys Chim Mol Interet Biol, F-31062 Toulouse 9, France

[3] CNRS, UMR 508, LBCMCP, F-31062 Toulouse 9, France

来源：

CHEMICAL BIOLOGY & DRUG DESIGN | 2011年 / 77卷 / 01期

关键词：

bisubstrate inhibitor; chemical biology; drug design; HAT; p300; SMALL-MOLECULE; CHROMATIN TRANSCRIPTION; SCORING FUNCTIONS; COENZYME-A; PROTEIN; DOCKING; HATS; IDENTIFICATION; ACETYLATION; EPIGENETICS;

D O I：

10.1111/j.1747-0285.2010.01056.x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Bisubstrate-type compound Lys-CoA has been shown to inhibit the p300 histone acetyl transferase activity efficiently and may constitute a lead compound for a novel class of anticancer therapeutics. Based on this strategy, we synthesized a series of CoA derivatives and evaluated these molecules for their activity as p300 histone acetyltransferases inhibitor. The best activity was obtained with compound 3 bearing a C-5 spacing linker that connects the CoA moiety to a tert-butyloxycarbonyl (Boc) group. Based on docking simulations, this inhibitor exhibits favorable interactions with two binding areas, namely pockets P1 and P2, within the active site.

引用

页码：86 / 92

页数：7

共 36 条

[1] Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription [J].