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A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct
Version 2 2023-06-12, 06:43
Version 1 2023-06-09, 02:39
journal contribution
posted on 2023-06-12, 06:43 authored by Cory A Ocasio, Mohan RajasekaranMohan Rajasekaran, Sarah Walker, Darren Le Grand, John SpencerJohn Spencer, Frances PearlFrances Pearl, Simon E Ward, Velibor Savic, Laurence PearlLaurence Pearl, Helfrid HocheggerHelfrid Hochegger, Antony OliverAntony OliverMASTL (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.
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Publication status
- Published
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- Published version
Journal
OncotargetISSN
1949-2553Publisher
Impact JournalsExternal DOI
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44Volume
7Page range
71182 -71197Department affiliated with
- BSMS Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2016-08-26First Open Access (FOA) Date
2016-08-26First Compliant Deposit (FCD) Date
2016-08-26Usage metrics
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