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A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct

Ocasio, Cory A., Rajasekaran, Mohan B., Walker, Sarah, Le Grand, Darren, Spencer, John, Pearl, Frances M.G., Ward, Simon, Savic, Velibor, Pearl, Laurence H., Hochegger, Helfrid and Oliver, Antony W. 2016. A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct. Oncotarget 7 (44) , pp. 71182-71197. 10.18632/oncotarget.11511

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Uncontrolled Keywords: kinase, inhibitor, Greatwall, ENSA, cancer
Publisher: Impact Journals LLC
ISSN: 1949-2553
Date of First Compliant Deposit: 9 October 2018
Date of Acceptance: 2 August 2016
Last Modified: 19 Jun 2019 13:22
URI: http://orca-mwe.cf.ac.uk/id/eprint/109274

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