Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10591093 | Bioorganic & Medicinal Chemistry Letters | 2014 | 6 Pages |
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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Authors
Matthew D. Cheeseman, Amir Faisal, Sydonia Rayter, Olivier R. Barbeau, Andrew Kalusa, Maura Westlake, Rosemary Burke, Michael Swan, Rob van Montfort, Spiros Linardopoulos, Keith Jones,