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 ORCID: https://orcid.org/0000-0002-8745-8377, 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:	03 May 2023 22:34
URI:	https://orca.cardiff.ac.uk/id/eprint/109274

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