Development of a sphingosine kinase 1 specific small-molecule inhibitor

被引：51

作者：

Hengst, Jeremy A. ^{[1
]}

Wang, XuJun ^{[1
]}

Sk, Ugir H. ^{[1
]}

Sharma, Arun K. ^{[1
]}

Amin, Shantu ^{[1
]}

Yun, Jong K. ^{[1
]}

机构：

[1] Penn State Univ, Coll Med, Dept Pharmacol, Hershey, PA 17033 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 24期

关键词：

Sphingosine kinase; Sphingosine; Sphingosine-1-phosphate; Small-molecule inhibitor; Hyperproliferative disease; Inflammatory disease; BREAST-CANCER-CELLS; APOPTOSIS; SPHINGOLIPIDS; GROWTH; THERAPEUTICS; NAPHTHALENE; TARGETS; BIOLOGY;

D O I：

10.1016/j.bmcl.2010.10.005

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The sphingolipid metabolic pathway represents a potential source of new therapeutic targets for numerous hyperproliferative/inflammatory diseases. Targets such as the sphingosine kinases (SphKs) have been extensively studied and numerous strategies have been employed to develop inhibitors against these enzymes. Herein, we report on the optimization of our novel small-molecule inhibitor SKI-I (N '-[(2-hydroxy-1-naphthyl) methylene]-3-(2-naphthyl)-1H-pyrazole-5-carbohydrazide) and the identification of a SphK1-specific analog, SKI-178, that is active in vitro and in vivo. This SphK1 specific small-molecule, non-lipid like, inhibitor will be of use to elucidate the roles of SphK1 and SphK2 in the development/progression of hyperproliferative and/or inflammatory diseases. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：7498 / 7502

页数：5

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