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Discovery of a small-molecule binder of the oncoprotein gankyrin that modulates gankyrin activity in the cell.

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Chattopadhyay, Anasuya 
O'Connor, Cornelius J 
Zhang, Fengzhi 
Galvagnion, Celine 
Galloway, Warren RJD 


Gankyrin is an ankyrin-repeat oncoprotein whose overexpression has been implicated in the development of many cancer types. Elevated gankyrin levels are linked to aberrant cellular events including enhanced degradation of tumour suppressor protein p53, and inhibition of gankyrin activity has therefore been identified as an attractive anticancer strategy. Gankyrin interacts with several partner proteins, and a number of these protein-protein interactions (PPIs) are of relevance to cancer. Thus, molecules that bind the PPI interface of gankyrin and interrupt these interactions are of considerable interest. Herein, we report the discovery of a small molecule termed cjoc42 that is capable of binding to gankyrin. Cell-based experiments demonstrate that cjoc42 can inhibit gankyrin activity in a dose-dependent manner: cjoc42 prevents the decrease in p53 protein levels normally associated with high amounts of gankyrin, and it restores p53-dependent transcription and sensitivity to DNA damage. The results represent the first evidence that gankyrin is a "druggable" target with small molecules.



Antineoplastic Agents, Aurora Kinase A, Benzenesulfonates, Calorimetry, Cell Cycle Proteins, Cell Line, Tumor, Cell Survival, DNA Damage, Escherichia coli, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Magnetic Resonance Spectroscopy, Mass Spectrometry, Microtubule-Associated Proteins, Neoplasms, Nuclear Proteins, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins, Rad51 Recombinase, Thermodynamics, Triazoles, Tumor Suppressor Protein p53

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Scientific Reports

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Nature Publishing Group
Engineering and Physical Sciences Research Council (EP/K039520/1)
The Royal Society (uf110479)
European Research Council (279337)
The work was supported by a grant from the Development Gap Fund (MRC Technology), a research grant from the Isaac Newton Trust, Cambridge and from the CORE charity. LSI acknowledges the support of a Senior Fellowship from the Medical Research Foundation. TR holds a Royal Society University Research Fellowship. The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ ERC grant agreement n° [279337/DOS].