GW843682, 5-(5,6-Dimethoxy-1H-benzimidazol-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carboxamide

Description

GW843682X is a reversible, cell-permeable polo-like kinase (PLK) inhibitor. It selectively inhibits Plk1 and Plk3 (IC₅₀s = 2.2 and 9.1 nM, respectively) over PDGFR1β, VEGFR2, Aurora A, and Cdk2/cyclin A (IC₅₀s = 160, 360, 4,800, and 7,600 nM, respectively), as well as over 30 other kinases, in a cell-free assay. GW843682X also inhibits Plk1 activity in vitro in HeLa cells (IC₅₀ = 0.14 μM in a reporter assay using chimeric Plk1). It inhibits growth in nine cancer cell lines in a panel (IC₅₀s = 0.11-0.7 μM) but not of PC3 human prostate cancer cells (IC₅₀ = 6.82 μM) or non-cancerous human diploid fibroblasts (HDFs; IC₅₀ = 6.14 μM). GW843682X inhibits growth of MES-SA human uterine sarcoma cells, as well as of the drug-resistant, P-glycoprotein-expressing MES-SA/Dx5 subline (IC₅₀s = 0.21 and 0.21 μM, respectively). It also inhibits the growth of patient-derived leukemia cells (IC₅₀s = <0.25-0.8 μM). GW843682X induces G₂/M cell cycle arrest and apoptosis of H460 human lung and PALL-2 and MOLM13 human leukemia cancer cells in a concentration-dependent manner.

Uses

GW843682X is a polo-like kinase-1 (PLK1) and polo-like kinase-3 (PLK3) inhibitor.

Definition

ChEBI: 5-(5,6-dimethoxy-1-benzimidazolyl)-3-[[2-(trifluoromethyl)phenyl]methoxy]-2-thiophenecarboxamide is a member of (trifluoromethyl)benzenes.

Biological Activity

Selective inhibitor of polo-like kinase 1 (PLK1) and polo-like kinase 3 (PLK3) (IC 50 values are 2.2 and 9.1 nM respectively). Displays > 100-fold selectivity over ~30 other kinases tested including cdk1 and cdk2. Inhibits proliferation of most tumor cells in vitro and is selective over normal diploid fibroblasts.

storage

Desiccate at +4°C

References

[1] TIMOTHY J LANSING. In vitro biological activity of a novel small-molecule inhibitor of polo-like kinase 1.[J]. Molecular Cancer Therapeutics, 2007, 6 2: 450-459. DOI: 10.1158/1535-7163.mct-06-0543
[2] T IKEZOE. A novel treatment strategy targeting polo-like kinase 1 in hematological malignancies[J]. Leukemia, 2009, 23 9: 1564-1576. DOI: 10.1038/leu.2009.94