Identification of Novel, Selective, and Stable Inhibitors of Class II Histone Deacetylases. Validation Studies of the Inhibition of the Enzymatic Activity of HDAC4 by Small Molecules as a Novel Approach for Cancer Therapy

被引：43

作者：

Ontoria, Jesus M. ^{[1
]}

Altamura, Sergio ^{[1
]}

Di Marco, Annalise ^{[1
]}

Ferrigno, Federica ^{[1
]}

Laufer, Ralph ^{[1
]}

Muraglia, Ester ^{[1
]}

Palumbi, Maria Cecilia ^{[1
]}

Rowley, Michael ^{[1
]}

Scarpelli, Rita ^{[1
]}

Schultz-Fademrecht, Carsten ^{[1
]}

Scrafini, Sergio ^{[1
]}

Steinkuehler, Christian ^{[1
]}

Jones, Philip ^{[1
]}

机构：

[1] P Angeletti SpA, IRBM MRL, I-00040 Pomezia, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 21期

关键词：

SUBEROYLANILIDE HYDROXAMIC ACID; PHASE-I; CATALYTIC-ACTIVITY; POTENT; TRIAL; DEPSIPEPTIDE; CHEMISTRY; INSIGHTS; REVEALS; LBH589;

D O I：

10.1021/jm900555u

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

5-Aryl-2-(trifluoroacetyl)thiophenes were identified as a new series of class II HDAC inhibitors (HDACi). Further development of this new series led to compounds such as 6h, a potent inhibitor of HDAC4 and HDAC6 (HDAC4 WT IC50 = 310 nM, HDAC6 IC50 = 70 nM) that displays 40-fold selectivity over HDAC1 and improved stability in HCT116 cancer cells (t(1/2)= 11 h). Compounds 6h and 2 show inhibition of alpha-tubulin deacetylation in HCT116 cells at 1 mu M concentration and antiproliferation effects only at concentrations where inhibition of historic H3 deacetylation is observed.

引用

页码：6782 / 6789

页数：8

共 2 条

[1] Novel Approaches Towards Designing of Isoform-Selective Inhibitors Against Class II Histone Deacetylases: The Acute Requirement for Targetted Anticancer Therapy
Ganai, Shabir Ahmad
[J]. CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2016, 16 (22) : 2441 - 2452
[2] Histone Deacetylase (HDAC) Inhibitors with a Novel Connecting Unit Linker Region Reveal a Selectivity Profile for HDAC4 and HDAC5 with Improved Activity against Chemoresistant Cancer Cells
Marek, Linda
Hamacher, Alexandra
Hansen, Finn K.
Kuna, Krystina
Gohlke, Holger
Kassack, Matthias U.
Kurz, Thomas
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (02) : 427 - 436

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