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 E, 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). 71182 -71197. ISSN 1949-2553

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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 rst 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 e cacy. 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
Schools and Departments: Brighton and Sussex Medical School > Brighton and Sussex Medical School
School of Life Sciences > Chemistry
School of Life Sciences > Sussex Centre for Genome Damage and Stability
Brighton and Sussex Medical School > Clinical and Experimental Medicine
Depositing User: Antony Oliver
Date Deposited: 26 Aug 2016 16:03
Last Modified: 21 Sep 2017 10:28
URI: http://sro.sussex.ac.uk/id/eprint/63037

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