GW843682X

GW843682X is a selective inhibitor of polo-like kinase 1 (PLK1) and polo-like kinase 3 (PLK3) (IC50 values are 2.2 and 9.1 nM respectively). GW843682X displays > 100-fold selectivity over ~30 other kinases tested including cdk1 and cdk2. GW843682X inhibits proliferation of most tumor cells in vitro and is selective over normal diploid fibroblasts.

The cytotoxic effect of GW843682X on nasopharyngeal carcinoma.[Pubmed:27198987]

Anticancer Agents Med Chem. 2016;16(12):1640-1645.

BACKGROUND: GW843682X is a publicly available anti-cancer compound by inhibiting Polo-like kinase. Previous studies revealed that GW843682X inhibited the proliferation of various tumor cell lines. In this study, the cytotoxic effect of GW843682X was investigated on cell proliferation, cell cycle and apoptosis of nasopharyngeal carcinoma 5-8F cells. METHODS: Cell morphological changes were observed by inverted microscopy. Cell proliferation was tested by CCK8 assay. Cell cycle arrest and apoptosis were tested by flow cytometry. The mechanism of apoptosis was investigated by RT-PCR to determine the mRNA expression of IAP-1, IAP-2, XIAP, and survivin. RESULTS: GW843682X resulted in remarkable cell morphological changes with the increase of drug concentrations. CCK8 assay revealed that GW843682X inhibited the proliferation and induced apoptosis of 5-8F cells in a dose-dependent manner (IC50=62.5-125nmol/L). After treating 5-8F cells with different doses of GW843682X for 12 h, G2/M phase cells significantly increased while G0/G1 phase cells remarkably decreased. Interestingly, GW843682X signi fi cantly inhibited the mRNA expression of IAP-1 and survivin, which function as key regulators of mitosis and programmed cell death, and is overexpressed in many tumor types. The mechanism of cytotoxic effect is partially due to the inhibition of IAP gene expression. CONCLUSION: These findings indicated that GW843682X exhibited remarkable cytotoxic effects on nasopharyngeal carcinoma 5-8F cells by down-regulating IAP gene expression, suggesting that GW843682X may become a novel therapeutic agent for nasopharyngeal carcinoma.

An in-vitro evaluation of the polo-like kinase inhibitor GW843682X against paediatric malignancies.[Pubmed:21637161]

Anticancer Drugs. 2011 Jul;22(6):531-42.

Polo-like kinase 1 (PLK1) is a regulator of mitosis and its upregulation in tumours is often associated with poor prognosis. Although PLK1 inhibitors have already entered phase 1 clinical trials, little is known about their impact on the treatment of paediatric malignancies. Thus, we evaluated the concept of PKL1 inhibition by testing the effects of the PLK1 inhibitor GW843682X alone and in combination with the topoisomerase 1 inhibitor, camptothecin, against a panel of 18 paediatric tumour cell lines. Cytotoxicity was evaluated by MTT test and by caspase 3/7 activation. Expression of target was confirmed by western blot analysis. Expression of ATP binding cassette transporters was analysed by quantitative real-time reverse transcription PCR. GW843682X significantly inhibited cell growth in all 18 cell lines. Concentrations, which inhibited cell growth by 50% compared with untreated controls after 72 h, ranged from 0.02 to 11.7 mumol/l. Apart from the N-Myc-amplified neuroblastoma cell lines, the osteosarcoma cell lines MNNG-HOS and OST, which are highly resistant to standard anticancer drugs, were sensitive to GW843682X. The toxicity of GW843682X was dependent neither on the ATP binding cassette drug transporter expression nor on the p53 mutation status. Neither synergistic nor antagonistic effects were observed for the combination of GW843682X and camptothecin in 14 cell lines. GW843682X showed considerable toxicity against a panel of paediatric tumour cell lines suggesting that PLK1 inhibitors under clinical development should be evaluated against paediatric malignancies too.

In vitro biological activity of a novel small-molecule inhibitor of polo-like kinase 1.[Pubmed:17267659]

Mol Cancer Ther. 2007 Feb;6(2):450-9.

Polo-like kinase 1 (PLK1) plays key roles in the regulation of mitotic progression, including mitotic entry, spindle formation, chromosome segregation, and cytokinesis. PLK1 expression and activity are strongly linked to proliferating cells. Many studies have shown that PLK1 expression is elevated in a variety of tumors, and high expression often correlates with poor prognosis. Using a variety of methods, including small-molecule inhibition of PLK1 function and/or activity, apoptosis in cancer cell lines, cell cycle arrest in normal cell lines, and antitumor activity in vivo have been observed. In the present study, we have examined the in vitro biological activity of a novel and selective thiophene benzimidazole ATP-competitive inhibitor of PLK1 and PLK3 (5-(5,6-dimethoxy-1H-benzimidazol-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}thioph ene-2-carboxamide, called compound 1). Compound 1 has low nanomolar activity against the PLK1 and PLK3 enzymes and potently inhibits the proliferation of a wide variety of tumor cell lines. In the lung adenocarcinoma cell line NCI-H460, compound 1 induces a transient G(2)-M arrest, mitotic spindle defects, and a multinucleate phenotype resulting in apoptosis, whereas normal human diploid fibroblasts arrest in G(2)-M and show little apoptosis. We also describe a cellular mechanistic assay that was developed to identify potent intracellular inhibitors of PLK1. In addition to its potential as a therapeutic agent for treating cancer, compound 1 is also a useful tool molecule for further investigation of the biological functions of PLK1 and PLK3.

GW843682X is a selective, ATP-competitive inhibitor of PLK1 and PLK3, with IC50s of 2.2 nM and 9.1 nM, respectively, and is also >100-fold selective against ∼30 other kinases.

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