Identification of pyrazolopyridazinones as PDEd inhibitors

被引：128

作者：

Papke, Bjoern ^{[1
]}

Murarka, Sandip ^{[2
]}

Vogel, Holger A. ^{[1
]}

Martin-Gago, Pablo ^{[2
]}

Kovacevic, Marija ^{[1
]}

Truxius, Dina C. ^{[1
]}

Fansa, Eyad K. ^{[3
]}

Ismail, Shehab ^{[3
,4
]}

Zimmermann, Gunther ^{[2
]}

Heinelt, Kaatje ^{[1
]}

Schultz-Fademrecht, Carsten ^{[5
]}

Al Saabi, Alaa ^{[5
]}

Baumann, Matthias ^{[5
]}

Nussbaumer, Peter ^{[5
]}

Wittinghofer, Alfred ^{[3
]}

Waldmann, Herbert ^{[2
,6
]}

Bastiaens, Philippe I. H. ^{[1
,6
]}

机构：

[1] Max Planck Inst Mol Physiol, Dept System Cell Biol, D-44227 Dortmund, Germany

[2] Max Planck Inst Mol Physiol, Dept Biol Chem, D-44227 Dortmund, Germany

[3] Max Planck Inst Mol Physiol, Struct Biol Grp, D-44227 Dortmund, Germany

[4] Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland

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

[6] TU Dortmund, Fac Chem & Chem Biol, D-44227 Dortmund, Germany

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

欧洲研究理事会;

关键词：

PLASMA-MEMBRANE; CANCER-THERAPY; RAS ONCOGENES; K-RAS; DELTA; ASSOCIATION; TRANSPORT; ARL2-GTP; REVEALS;

D O I：

10.1038/ncomms11360

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The prenyl-binding protein PDEd is crucial for the plasma membrane localization of prenylated Ras. Recently, we have reported that the small-molecule Deltarasin binds to the prenyl-binding pocket of PDEd, and impairs Ras enrichment at the plasma membrane, thereby affecting the proliferation of KRas-dependent human pancreatic ductal adenocarcinoma cell lines. Here, using structure-based compound design, we have now identified pyrazolopyridazinones as a novel, unrelated chemotype that binds to the prenyl-binding pocket of PDEd with high affinity, thereby displacing prenylated Ras proteins in cells. Our results show that the new PDEd inhibitor, named Deltazinone 1, is highly selective, exhibits less unspecific cytotoxicity than the previously reported Deltarasin and demonstrates a high correlation with the phenotypic effect of PDEd knockdown in a set of human pancreatic cancer cell lines.

引用

页数：9

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