A First Generation Inhibitor of Human Greatwall Kinase, Enabled by Structural and Functional Characterisation of a Minimal Kinase Domain Construct

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 Aug 27

PMID 27563826

Citations 20

Authors

Cory A Ocasio

Mohan B Rajasekaran

Sarah Walker

Darren Le Grand

John Spencer

Frances M G Pearl

Simon E Ward

Velibor Savic

Laurence H Pearl

Helfrid Hochegger

Antony W Oliver

Affiliations

Soon will be listed here.

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.

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