The wild-type p53-induced phosphatase (Wip1, encoded by PPM1D), an oncogenic type 2C serine/threonine phosphatase common to multiple cancers, negatively regulates key proteins in the DNA damage–response pathway. GSK2830371 is the first orally active, allosteric inhibitor of Wip1 with an IC50 value of 6 nM. GSK2830371 potently inhibited Wip1 (2–420) dephosphorylation of FDP and the endogenous substrates phospho-p38 MAPK (T180) with IC50 values of 6 nM and 13 nM, respectively. In the PPM1D-amplified MCF7 breast carcinoma cells, treatment with GSK2830371 for 24 h increased phosphorylation of substrates in a concentration-dependent manner. Treatment of MX-1 and MCF7 cells (Wip1 amplified, p53 wild type) with GSK2830371 caused concentration-dependent effects in cell growth assays. In a 7-d cell growth assay, GSK2830371 showed antiproliferative activity in a subset of lymphoid cell lines, all of which carry a wild-type TP53 allele. Co-treatment of DOHH2 and MX-1 tumor cells with the combination of GSK2830371 with doxorubicin, an anticancer agent shown to induce DNA damage, resulted in a synergistic antiproliferative effect. Unexpectively, treatment with GSK2830371 for 24 h also produced a rapid decrease in Wip1 protein concentrations. In a pharmacodynamic assay, orally administered GSK2830371 increased phosphorylation of Chk2 (T68) and p53 (S15) and decreased Wip1 protein concentrations in DOHH2 tumors. Following 14 d of oral dosing at 150 mg per kg body weight, BID (twice daily) and TID (thrice daily), GSK2830371 inhibited the growth of DOHH2 tumor xenografts by 41% and 68%, respectively[2].
GSK 2830371 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
Escherichia coli BL21 (DE3) pLysS cells
Function assay
Inhibition of His-tagged PPM1D (1 to 420 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) pLysS cells using Ac-VEPPLS(P)QETFSDLW-NH2 substrate, IC50=0.0863 μM
26358280
MCF7 cells
Function assay
24 h
Inhibition of cell proliferation of human MCF7 cells incubated for 24 hrs, IC50=9.5 μM
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