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A highly potent clickable probe for cellular imaging of MDM2 and assessing dynamic responses to MDM2-p53 inhibition

Lookup NU author(s): Honorine Lebraud, Dr Richard NobleORCiD, Nicole Phillips, Dr Yan Zhao, Professor Herbie Newell, Professor John LunecORCiD, Professor Steve Wedge


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MDM2 is a key negative regulator of the p53 tumour suppressor. Direct binding of MDM2 to p53, represses the protein’s transcriptional activity and induces its polyubiquitination, targeting it for degradation by the proteasome. Consequently, small molecule inhibitors that antagonise MDM2-p53 binding, such as RG7388, have progressed into clinical development aiming to reactivate p53 function in TP53 wild-type tumours. Here, we describe the design, synthesis and biological evaluation of a trans-cyclooctene tagged derivative of RG7388, RG7388-TCO, which showed high cellular potency and specificity for MDM2. The in-cell reaction of RG7388-TCO with a tetrazine-tagged BODIPY dye enabled fluorescence imaging of endogenous MDM2 in SJSA-1 and T778 tumour cells. RG7388-TCO was also used to pull down MDM2 by reaction with tetrazine-tagged agarose beads in SJSA-1 lysates. The data presented show that RG733-TCO enables precise imaging of MDM2 in cells and can permit a relative assessment of target engagement and MDM2-p53 antagonism in vitro.

Publication metadata

Author(s): Lebraud H, Noble R, Phillips N, Hearn K, Castro J, Zhao Y, Newell DR, Lunec J, Wedge S, Heightman TD

Publication type: Article

Publication status: Published

Journal: Bioconjugate Chemistry

Year: 2018

Volume: 29

Issue: 6

Pages: 2100-2106

Online publication date: 31/05/2018

Acceptance date: 30/05/2018

ISSN (print): 1043-1802

ISSN (electronic): 1520-4812

Publisher: American Chemical Society


DOI: 10.1021/acs.bioconjchem.8b00315


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