Small molecules that bind the Mdm2 RING stabilize and activate p53

Roxburgh, P. , Hock, A.K., Dickens, M.P., Mezna, M., Fischer, P.M. and Vousden, K.H. (2013) Small molecules that bind the Mdm2 RING stabilize and activate p53. Carcinogenesis, 34(3), pp. 791-798. (doi: 10.1093/carcin/bgs092)

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p53 is a tumour suppressor that responds to a variety of stresses such as oncogenes and DNA damage by activating its transcriptional targets to allow repair or elimination of damaged cells. In the absence of stress signals p53 needs to be kept in check and this is achieved by the E3 ligase MDM2. For tumours that retain wild-type p53 therapeutic strategies aimed at removing the inhibitory activity of MDM2 on p53 are under development, and to date have focused on drugs that prevent the binding of p53 to MDM2. Here we report the analysis of a group of synthetic analogues derived from 5-deazaflavin compounds previously identified in a screen as inhibitors of MDM2 autoubiquitination. Using measurement of surface plasmon resonance we demonstrated that active 5-deazaflavin analogues bind to the MDM2 RING, while inactive compounds show no binding. In cellular assays, these active MDM2 RING binding compounds inhibited the ubiquitination of p53, stabilized p53, led to increased expression of p53 targets and caused corresponding cell cycle effects. Deazaflavin analogues therefore function to activate p53 through a novel mechanism, by inhibiting the E3 ligase activity of MDM2 in a manner that involves binding to the MDM2 RING.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Hock, Dr Andreas and Mezna, Dr Mokdad and Vousden, Karen and Roxburgh, Dr Patricia
Authors: Roxburgh, P., Hock, A.K., Dickens, M.P., Mezna, M., Fischer, P.M., and Vousden, K.H.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Carcinogenesis
ISSN (Online):1460-2180
Published Online:02 February 2012

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