Cheeseman, M. D., Faisal, A., Rayter, S., Barbeau, O. R., Kalusa, A., Westlake, M., Burke, R., Swan, M., van Montfort, R., Linardopoulos, S., Jones, K. (2014) Targeting the PPM1D phenotype; 2,4-bisarylthiazoles cause highly selective apoptosis in PPM1D amplified cell-lines. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 24 (15). pp. 3469-3474. ISSN 0960-894X

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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. (C) 2014 Published by Elsevier Ltd.

Item Type:	Article
Authors (ICR Faculty only):	Jones, Keith and Linardopoulos, Spiros and Van Montfort, Rob
All Authors:	Cheeseman, M. D., Faisal, A., Rayter, S., Barbeau, O. R., Kalusa, A., Westlake, M., Burke, R., Swan, M., van Montfort, R., Linardopoulos, S., Jones, K.
Additional Information:	ISI Document Delivery No.: AL6FT Times Cited: 0 Cited Reference Count: 22 Cheeseman, Matthew D. Faisal, Amir Rayter, Sydonia Barbeau, Olivier R. Kalusa, Andrew Westlake, Maura Burke, Rosemary Swan, Michael van Montfort, Rob Linardopoulos, Spiros Jones, Keith Cancer Research UK [C309/A8274, C309/A11566]; Institute of Cancer Research This work was supported by Cancer Research UK grant numbers C309/A8274 and C309/A11566, and by The Institute of Cancer Research. 0 PERGAMON-ELSEVIER SCIENCE LTD OXFORD BIOORG MED CHEM LETT
Uncontrolled Keywords:	PPM1D Phenotype Apoptosis p53 2,4-Bisarylthiazole BREAST-CANCER WIP1 INHIBITOR ASSAY AMPLIFICATION PHOSPHATASES DISCOVERY P53
Research teams:	ICR divisions > Breast Cancer Research > Drug Target Discovery ICR divisions > Cancer Therapeutics > Drug Target Discovery ICR divisions > Cancer Therapeutics > Hit Discovery & Structural Design ICR divisions > Structural Biology > Hit Discovery & Structural Design ICR divisions > Breast Cancer Research > Target Discovery & Apoptosis ICR divisions > Cancer Therapeutics > Target Discovery & Apoptosis ICR divisions > Cancer Therapeutics > Medicinal Chemistry 3 ICR divisions > Cancer Therapeutics > Structure-Based Drug Design ICR divisions > Structural Biology > Structure-Based Drug Design
Depositing User:	Users 11 not found.
Date Deposited:	04 Sep 2014 11:52
Last Modified:	04 Sep 2014 11:52
URI:	http://publications.icr.ac.uk/id/eprint/13440

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