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Ocasio, Cory A; Rajasekaran, Mohan B; Walker, Sarah; Le Grand, Darren; Spencer, John; Pearl, Frances M G; Ward, Simon E; Savic, Velibor; Pearl, Laurence H; Hochegger, Helfrid; Oliver, Antony W (2016)
Publisher: Impact Journals
Journal: Oncotarget
Languages: English
Types: Article
Subjects: kinase, Greatwall, inhibitor, ENSA, cancer, Research Paper
MASTL (microtubule-associated serine/threonine kinase-like), more commonly known as Greatwall (GWL), has been proposed as a novel cancer therapy target. GWL plays a crucial role in mitotic progression, via its known substrates ENSA/ARPP19, which when phosphorylated inactivate PP2A/B55 phosphatase. When over-expressed in breast cancer, GWL induces oncogenic properties such as transformation and invasiveness. Conversely, down-regulation of GWL selectively sensitises tumour cells to chemotherapy. Here we describe the first structure of the GWL minimal kinase domain and development of a small-molecule inhibitor GKI-1 (Greatwall Kinase Inhibitor-1). In vitro, GKI-1 inhibits full-length human GWL, and shows cellular efficacy. Treatment of HeLa cells with GKI-1 reduces ENSA/ARPP19 phosphorylation levels, such that they are comparable to those obtained by siRNA depletion of GWL; resulting in a decrease in mitotic events, mitotic arrest/cell death and cytokinesis failure. Furthermore, GKI-1 will be a useful starting point for the development of more potent and selective GWL inhibitors.

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Funded by projects

  • EC | GREATWALL KINASE

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