Targeting the PPM1D phenotype; 2,4-bisarylthiazoles cause highly selective apoptosis in PPM1D amplified cell-lines

被引：6

作者：

Cheeseman, Matthew D. ^{[1
]}

Faisal, Amir ^{[1
]}

Rayter, Sydonia ^{[1
]}

Barbeau, Olivier R. ^{[1
]}

Kalusa, Andrew ^{[1
]}

Westlake, Maura ^{[1
]}

Burke, Rosemary ^{[1
]}

Swan, Michael ^{[1
]}

van Montfort, Rob ^{[1
]}

Linardopoulos, Spiros ^{[1
]}

Jones, Keith ^{[1
]}

机构：

[1] Inst Canc Res, CRUK Canc Therapeut Unit, London SM2 5NG, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 15期

关键词：

PPM1D; Phenotype; Apoptosis; p53; 2,4-Bisarylthiazole; BREAST-CANCER; INHIBITOR; ASSAY; WIP1; AMPLIFICATION; PHOSPHATASES; DISCOVERY;

D O I：

10.1016/j.bmcl.2014.05.067

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The metal-dependent phosphatase PPM1D (WIP1) is an important oncogene in cancer, with over-expression of the protein being associated with significantly worse clinical outcomes. In this communication we describe the discovery and optimization of novel 2,4-bisarylthiazoles that phenocopy the knockdown of PPM1D, without inhibiting its phosphatase activity. These compounds cause growth inhibition at nanomolar concentrations, induce apoptosis, activate p53 and display impressive cell-line selectivity. The results demonstrate the potential for targeting phenotypes in drug discovery when tackling challenging targets or unknown mechanisms. (C) 2014 Published by Elsevier Ltd.

引用

页码：3469 / 3474

页数：6

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