Polo-like kinase 1 (Plk1) is a conserved serine/threonine kinase that plays an essential role in regulating the many processes involved in mitotic entry and progression. In humans, Plk1 is expressed primarily during late G2 and M phases and, in conjunction with Cdk1/cyclin B1, acts as master regulatory kinases for the myriad protein substrates involved in mitosis. Plk1 overexpression is strongly associated with cancer and has been correlated with poor prognosis in a broad range of human tumor types. GSK461364 is a potent, selective, reversible, ATP-competitive Plk1 inhibitor with a Ki value of 2.2 nM. To further explore selectivity, GSK461364 was tested against an in-house panel of 48 kinases. GSK461364 had at least 1,000-fold selectivity for Plk1 over the majority of kinases tested. In a NSCLC line A549, treatment with GSK461364 above 10 nmol/L for 20 hours caused increased 4N DNA content indicating G2-M arrest. With extended exposure duration, increased sub-2N DNA indicating increased cell death was observed for GSK461364 concentrations of >10 nmol/L. In A549 cells, at 20 nmol/L GSK461364 for 16 hours, a significant increase in mitotic cells was evident. In a proliferation assay, 89% of cell lines (66 of 74 lines) responded to GSK461364 with a gI50 (concentration required to inhibit 50% cell growth) of ≤100 nmol/L. GSK461364 was dosed i.p. in mice bearing Colo205 (colorectal) xenograft tumors, higher intermittent dosing with a q4dx3 (one dose every 4 days repeated thrice) schedule at 100 mg/kg resulted in 18 days TGD (tumor growth delay) and one PR (partial regression) out of five mice treated. More frequent lower dosing with 50 mg/kg q2dx6 schedule resulted in longer TGD (39 days) and 2PR. Extending the schedule of 50 mg/kg q2dx12 resulted in longer TGD (62 days) with one CR and 3PR observed, efficacy approaching the antitumor activity of the positive control agent paclitaxel[2].
GSK461364 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
human MV4-11 cells
Cytotoxicity assay
24 h
Cytotoxicity against human MV4-11 cells after 24 hrs by CellTiter-Blue assay, GI50=0.679 μM
United Kingdom
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United Kingdom
... 展开 >> GSK Investigational Site
Sutton, Surrey, United Kingdom, SM2 5PT
GSK Investigational Site
Belfast, Northern Ireland, United Kingdom, BT9 7AB
GSK Investigational Site
London, United Kingdom, W12 0NN 收起 <<
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