title: Targeting the PPM1D phenotype; 2,4-bisarylthiazoles cause highly selective apoptosis in PPM1D amplified cell-lines.
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.
authors: CRUK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors: Matthew D
authors: MD
authors: Cheeseman
authors: CRUK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors: Amir
authors: A
authors: Faisal
authors: CRUK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors: Sydonia
authors: S
authors: Rayter
authors: CRUK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors: Olivier R
authors: OR
authors: Barbeau
authors: CRUK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors: Andrew
authors: A
authors: Kalusa
authors: CRUK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors: Maura
authors: M
authors: Westlake
authors: CRUK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors: Rosemary
authors: R
authors: Burke
authors: CRUK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors: Michael
authors: M
authors: Swan
authors: CRUK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors: Rob
authors: R
authors: van Montfort
authors: CRUK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors: Spiros
authors: S
authors: Linardopoulos
authors: CRUK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK. Electronic address: keith.jones@icr.ac.uk.
authors: Keith
authors: K
authors: Jones
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D010641:Phenotype; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C
keywords: 2,4-Bisarylthiazole; Apoptosis; PPM1D; Phenotype; p53