title: A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct.
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.
authors: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.|Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
authors: Cory A
authors: CA
authors: Ocasio
authors: Cancer Research UK DNA Repair Enzymes Group, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
authors: Mohan B
authors: MB
authors: Rajasekaran
authors: Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
authors: Sarah
authors: S
authors: Walker
authors: Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
authors: Darren
authors: D
authors: Le Grand
authors: School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
authors: John
authors: J
authors: Spencer
authors: School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
authors: Frances M G
authors: FM
authors: Pearl
authors: Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
authors: Simon E
authors: SE
authors: Ward
authors: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.|Brighton and Sussex Medical School, University of Sussex, Falmer, Brighton, UK.
authors: Velibor
authors: V
authors: Savic
authors: Cancer Research UK DNA Repair Enzymes Group, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
authors: Laurence H
authors: LH
authors: Pearl
authors: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
authors: Helfrid
authors: H
authors: Hochegger
authors: Cancer Research UK DNA Repair Enzymes Group, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
authors: Antony W
authors: AW
authors: Oliver
mesh_terms: D003460:Crystallization; D006367:HeLa Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010766:Phosphorylation; D000072417:Protein Domains; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D008869:Microtubule-Associated Proteins; D047428:Protein Kinase Inhibitors; C555237:MASTL protein, human; D017346:Protein Serine-Threonine Kinases
keywords: ENSA; cancer; inhibitor; kinase; Greatwall