5 research outputs found

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

    Get PDF
    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.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]

    ICR ANNUAL REPORT 2020 (Volume 27)[All Pages]

    Get PDF
    This Annual Report covers from 1 January to 31 December 202

    NASH and Systemic Complications

    Get PDF
    Nonalcoholic fatty liver disease (NAFLD) is known as the hepatic manifestation of the metabolic syndrome, and while most patients develop simple steatosis, up to one-third can develop nonalcoholic steatohepatitis (NASH). NASH is a chronic inflammatory condition of the liver that can further progress to fibrosis and cirrhosis, which may eventually lead to liver failure and death. While we have increased our mechanistic knowledge regarding the pathogenesis of NASH within the last decade, treatment options are still limited and liver biopsies have remained the gold standard for diagnosis. To achieve major clinical breakthroughs for NASH patients, it is not sufficient to use a single animal model, since each model has specific limitations. Furthermore, we should rely more on alternative models such as organ-on-a-chip, which will enable us to explore unknown aspects of disease pathogenesis much faster and serve as clinically relevant surrogates for murine models. Another important direction for the improvement of patient health is to pay more attention to extrahepatic, organ-specific and systemic effects, which are associated with NASH. The articles in this Special Issue include an up-to-date overview of the rapidly developing technologies, novel targets for intervention and insights in the field in NASH. Additionally, these articles describe the major challenges in the field, strategies to overcome them and suggestions for future directions. To improve patient’s outcome, clinicians, as well as scientists with biomedical, nutrition, physics and mathematics backgrounds, should join forces. Although challenges remain, the future of the field seems promising as these novel technologies and developments are expected to lead to progress in NASH
    corecore