A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct
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Cory A. Ocasio1,3,*, Mohan B. Rajasekaran2,*, Sarah Walker3, Darren Le Grand3, John Spencer4, Frances M.G. Pearl4, Simon E. Ward3, Velibor Savic1,5, Laurence H. Pearl2, Helfrid Hochegger1 and Antony W. Oliver2
1 Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK
2 Cancer Research UK DNA Repair Enzymes Group, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK
3 Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK
4 School of Life Sciences, University of Sussex, Falmer, Brighton, UK
5 Brighton and Sussex Medical School, University of Sussex, Falmer, Brighton, UK
* The authors wish it to be known, that in their opinion, the first 2 authors should be regarded as joint first authors
Cory A. Ocasio, email:
Helfrid Hochegger, email:
Antony W. Oliver, email:
Keywords: kinase, inhibitor, Greatwall, ENSA, cancer
Received: July 20, 2016 Accepted: August 02, 2016 Published: August 22, 2016
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.
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