Development of Selective, Potent RabGGTase Inhibitors

被引：31

作者：

Stigter, E. Anouk ^{[2
,3
]}

Guo, Zhong ^{[1
]}

Bon, Robin S. ^{[2
]}

Wu, Yao-Wen ^{[1
]}

Choidas, Axel ^{[4
]}

Wolf, Alexander ^{[4
]}

Menninger, Sascha ^{[1
]}

Waldmann, Herbert ^{[2
,3
]}

Blankenfeldt, Wulf ^{[1
]}

Goody, Roger S. ^{[1
]}

机构：

[1] Max Planck Inst Mol Physiol, Dept Phys Biochem, D-44227 Dortmund, Germany

[2] Univ Bayreuth, Dept Biol Chem, D-95447 Bayreuth, Germany

[3] Tech Univ Dortmund, Fak Chem, Fachbereich Biol Chem, D-44227 Dortmund, Germany

[4] Lead Discovery Ctr GmbH, D-44227 Dortmund, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 19期

基金：

欧洲研究理事会;

关键词：

FARNESYL TRANSFERASE INHIBITORS; RAB GTPASES; PROTEIN FARNESYLTRANSFERASE;

D O I：

10.1021/jm300624s

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Members of the Ras superfamily of small GTPases are frequently mutated in cancer. Therefore, inhibitors have been developed to address the acitivity of these GTPases by inhibiting their prenylating enzymes FTase, GGTase I, and RabGGTase. In contrast to FTase and GGTase I, only a handful of RabGGTase inhibitors have been developed. The most active RabGGTase inhibitor known until recently was an FTase inhibitor which hit RabGGTase as an off-target. We recently reported our efforts to tune the selectivity of these inhibitors toward RabGGTase. Here we describe an extended set of selective inhibitors. The requirements for selective RabGGTase inhibitors are described in detail, guided by multiple crystal structures. In order to relate in vitro and cellular activity, a high-throughput assay system to detect the attachment of [H-3]geranylgeranyl groups to Rab was used. Selective RabGGTase inhibition allows the establishment of novel drug discovery programs aimed at the development of anticancer therapeutics.

引用

页码：8330 / 8340

页数：11