GW843682X PLK inhibitor

GW 843682X is a submicromolar inhibitor of proliferation of most tumour cells in culture, a notable exception being PC-3, a prostate carcinoma cell line. GW 843682X is also selective for tumour cells compared with normal diploid fibroblasts (HDF), with >10-fold difference in potency. GW 843682X is equipotent (∼200 nmol/L) against MES-SA/DX5 and the parental line MES-SA, suggesting that the compound is not effectively removed by the P-glycoprotein efflux pump in the cell. GW 843682X dose-dependently inhibits the phosphorylation of Ser15-p53 by PLK1 in HeLa cells expressing the tet-inducible chimeric p53-PLK1 protein. GW 843682X enhances HDF cell outgrowth with 30% at 3.3 μM and is able to enhance H460 outgrowth at lowest concentration of 0.37 μM. GW 843682X results in a strong G2-M arrest at 3 μM and very little G2-M arrest is observed at 1 μM in HDF cells. GW 843682X (3 μM) shows a reduced G2-M arrest, but there is an increase in sub-2N DNA content in H460 cells. GW 843682X (0.5 μM) results in cells that are larger in size than the untreated H460 cells and has multiple nuclei. [1] GW 843682X inhibits PLK1, PLK2, PLK3 and PLK4 with Ki values of 4.8 nM, 3.8 nM, 8 nM and 0.163 μM, respectively. [2] GW 843682X (1 μM) interferes with the localization of endogenous MyoGEF at the central spindle in HeLa cells. GW 843682X (1 μM) disrupts the localization of GFP-MyoGEF-wt (GFP-WT), GFP-MyoGEF-T574A (GFP-T574A), and GFP-MyoGEF-T574E (GFP-T574E) to the central spindle in HeLa cell. [3] GW-843682X causes identical premature midzone assembly and protein recruitment, suggesting that the drug effect is specific to PLK1 inhibition. GW 843682X (200 nM) causes microtubule bundling and central spindlin and PRC1 recruitments in equator in HeLa cells. [4]