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

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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 Oliver
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Oncotarget

ISSN

1949-2553

Publisher

Impact Journals

Issue

44

Volume

7

Page range

71182 -71197

Department affiliated with

  • BSMS Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2016-08-26

First Open Access (FOA) Date

2016-08-26

First Compliant Deposit (FCD) Date

2016-08-26

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