2. Academic Validation
  3. A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct

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

  • Oncotarget. 2016 Nov 1;7(44):71182-71197. doi: 10.18632/oncotarget.11511.
Cory A Ocasio 1 2,  Mohan B Rajasekaran 3,  Sarah Walker 2,  Darren Le Grand 2,  John Spencer 4,  Frances M G Pearl 4,  Simon E Ward 2,  Velibor Savic 1 5,  Laurence H Pearl 3,  Helfrid Hochegger 1,  Antony W Oliver 3
Affiliations

Affiliations

  • 1 Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
  • 2 Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
  • 3 Cancer Research UK DNA Repair Enzymes Group, Genome Damage and Stability 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.
PMID: 27563826 DOI: 10.18632/oncotarget.11511
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.

Keywords

ENSA; cancer; inhibitor; kinase; Greatwall.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-100521
    99.89%, Greatwall抑制剂
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z