Incorporation of Fluorinated Phenylalanine Generates Highly Specific Inhibitor of Proteasome's Chymotrypsin-like Sites

被引：32

作者：

Geurink, Paul P. ^{[1
,2
]}

Liu, Nora ^{[1
,2
]}

Spaans, Michiel P. ^{[1
,2
]}

Downey, Sondra L. ^{[3
]}

van den Nieuwendijk, Adrianus M. C. H. ^{[1
,2
]}

van der Marel, Gijsbert A. ^{[1
,2
]}

Kisselev, Alexei F. ^{[3
]}

Florea, Bogdan I. ^{[1
,2
]}

Overkleeft, Herman S. ^{[1
,2
]}

机构：

[1] Leiden Inst Chem, NL-2333 CC Leiden, Netherlands

[2] Netherlands Prote Ctr, Gorlaeus Labs, NL-2333 CC Leiden, Netherlands

[3] Dartmouth Med Sch, Dept Pharmacol & Toxicol, Lebanon, NH 03756 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 05期

关键词：

CASPASE-LIKE SITES; SUBSTRATE-SPECIFICITY; SELECTIVE INHIBITOR; POTENT; CELLS; ACIDS;

D O I：

10.1021/jm9015685

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Proteasomal processing is conducted by three individual catalytic subunits, namely beta 1, beta 2, and beta 5. Subunit-specific inhibitors are useful tools In dissecting the role of these individual Subunits and are leads toward the development of antitumor agents. We here report that the presence of fluorinated phenyl-alanine derivatives in peptide based proteasome inhibitors has a profound effect on inhibitor potency and selectivity, Specifically, compound 4a emerges as one of the most beta 5 specific inhibitors known to date.

引用

页码：2319 / 2323

页数：5

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