Targeting the PPM1D phenotype; 2,4-bisarylthiazoles cause highly selective apoptosis in PPM1D amplified cell-lines.
Bioorg Med Chem Lett
; 24(15): 3469-74, 2014 Aug 01.
Article
em En
| MEDLINE
| ID: mdl-24953599
ABSTRACT
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.
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MEDLINE
Assunto principal:
Tiazóis
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Apoptose
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Fosfoproteínas Fosfatases
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Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article