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 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HEL
5, 10, 20 µM
24, 48, 72 hours
WIP1i did not significantly affect HEL cell viability
Biomedicines. 2021 Apr 6;9(4):388.
U2OS
2.5 µM
4 hours
GSK2830371 induced degradation of full-length and truncated WIP1
Mol Cancer Ther. 2016 Mar;15(3):379-91.
IMR-32
50 µM
0–8 hours
GSK2830371 increased p53 activity and induced Chk2/p53-mediated apoptosis in p53 wild-type NB cells, but not in the p53 mutant SK-N-AS cell line.
Sci Rep. 2016 Dec 19;6:38011.
SH-SY5Y
50 µM
0–8 hours
GSK2830371 increased p53 activity and induced Chk2/p53-mediated apoptosis in p53 wild-type NB cells, but not in the p53 mutant SK-N-AS cell line.
Sci Rep. 2016 Dec 19;6:38011.
SK-N-AS
50 µM
0–8 hours
GSK2830371 did not significantly increase p53 activity in the p53 mutant SK-N-AS cell line.
Sci Rep. 2016 Dec 19;6:38011.
MV-4-11
5, 10, 20 µM
24, 48, 72 hours
WIP1i significantly reduced MV-4-11 cell viability, with a 78.2% reduction at 20 µM after 72 h
Biomedicines. 2021 Apr 6;9(4):388.
MOLM-13
5, 10, 20 µM
24, 48, 72 hours
WIP1i did not significantly affect MOLM-13 cell viability
Biomedicines. 2021 Apr 6;9(4):388.
OCI-AML3
5, 10, 20 µM
24, 48, 72 hours
WIP1i significantly reduced OCI-AML3 cell viability, with a 57.6% reduction at 20 µM after 72 h
Biomedicines. 2021 Apr 6;9(4):388.
NOMO-1
5, 10, 20 µM
24, 48, 72 hours
WIP1i did not significantly affect NOMO-1 cell viability
Biomedicines. 2021 Apr 6;9(4):388.
KASUMI-1
5, 10, 20 µM
24, 48, 72 hours
WIP1i did not significantly affect KASUMI-1 cell viability
Biomedicines. 2021 Apr 6;9(4):388.
HCT116+/+
2.5 µM
4 hours
GSK2830371 induced degradation of full-length and truncated WIP1
Mol Cancer Ther. 2016 Mar;15(3):379-91.
DIPG7 cells
5 µM
48 hours
GSK2830371 significantly reduced proliferation of DIPG7 cells.
Neuro Oncol. 2019 Jun 10;21(6):786-799.
DIPG VI-PPM1D-L513* cells
5 µM
48 hours
GSK2830371 significantly reduced proliferation of DIPG VI-PPM1D-L513* cells.
Neuro Oncol. 2019 Jun 10;21(6):786-799.
Secondary follicles
0, 0.1, 1.0, 5.0, 10.0 µM
6 days
Inhibition of WIP1 phosphatase activity impairs follicular development and oocyte quality.
Cells. 2022 Dec 3;11(23):3920.
RBE
2.5 µM
72 and 96 hours
GSK2830371 significantly enhanced the growth inhibitory activity of RG7388, evidenced by increased growth inhibition and cytotoxicity.
Am J Cancer Res. 2022 Sep 15;12(9):4399-4410.
SK-Hep-1
2.5 µM
72 and 96 hours
GSK2830371 significantly enhanced the growth inhibitory activity of RG7388, evidenced by increased growth inhibition and cytotoxicity.
Am J Cancer Res. 2022 Sep 15;12(9):4399-4410.
A375
2.5 µM
72 hours
GSK2830371 potentiated the growth-inhibitory and clonogenic cell killing effects of MDM2 inhibitors in p53WT but not p53MUT melanoma cells, indicating the potentiation worked in a p53-dependent manner.
Br J Cancer. 2018 Feb 20;118(4):495-508.
WM35
2.5 µM
72 hours
GSK2830371 potentiated the growth-inhibitory and clonogenic cell killing effects of MDM2 inhibitors in p53WT but not p53MUT melanoma cells, indicating the potentiation worked in a p53-dependent manner.
Br J Cancer. 2018 Feb 20;118(4):495-508.
C8161
2.5 µM
72 hours
GSK2830371 potentiated the growth-inhibitory and clonogenic cell killing effects of MDM2 inhibitors in p53WT but not p53MUT melanoma cells, indicating the potentiation worked in a p53-dependent manner.
Br J Cancer. 2018 Feb 20;118(4):495-508.
MES-SA
2.5 µM
72 hours
GSK2830371 significantly potentiated the growth inhibitory effects of RG7388 and HDM201, significantly reducing GI50 values.
Cancers (Basel). 2021 Dec 21;14(1):14.
SK-UT-1
2.5 µM
72 hours
GSK2830371 did not show significant growth inhibitory effects in p53-mutant SK-UT-1 cells.
Cancers (Basel). 2021 Dec 21;14(1):14.
MCF-7
2.5 µM
8 hours
GSK2830371 induced WIP1 degradation, p53 stabilization, and increased p53Ser15 phosphorylation
Mol Cancer Ther. 2016 Mar;15(3):379-91.
MCF-10A cells
0.5 µM
GSK2830371 induced p38 and Hsp27 phosphorylation in MCF-10A cells and reversed Her2-induced disseminating phenotypes and activation and nuclear translocation of β-catenin.
Oncogene. 2020 Oct;39(40):6313-6326.
MMTV-Her2 cells
0.5 µM
GSK2830371 upregulated phosphorylation of p38, MK2 and Hsp27-Ser86 and downregulated the levels of the Src phosphorylated and the active forms of β-catenin, increased E-cadherin junctions in organoids, and reduced percentage of invasive organoids in MMTV-Her2 cells.
Oncogene. 2020 Oct;39(40):6313-6326.
GSK 2830371 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
Orthotopic xenograft NB mouse model
Intraperitoneal injection
25 mg/kg
Once daily for 21 days
GSK2830371 significantly inhibited neuroblastoma growth and induced Chk2/p53-mediated apoptosis in vivo.
Sci Rep. 2016 Dec 19;6:38011.
NSG mice
DIPG7 cells orthotopic xenograft model
Brainstem injection
5 μM
Single dose, observed until symptomatic
GSK2830371 significantly extended the survival of NSG mice xenografted with DIPG7 cells, suppressed tumor proliferation, and increased apoptosis.
Neuro Oncol. 2019 Jun 10;21(6):786-799.
Mice
C57BL/6j
Oral
7.5 mg/kg, 15 mg/kg
Twice daily for 14 days
Inhibition of WIP1 phosphatase activity induces irregular estrous cycles, fertility declines, and decreased ovarian reserve through triggering excessive follicular atresia and primordial follicle activation.
Cells. 2022 Dec 3;11(23):3920.
NOD/SCID mice
SK-Hep-1 xenograft model
Oral gavage
75 mg/kg
Twice daily for two weeks
The combination of GSK2830371 and RG7388 significantly inhibited tumor growth, with the combination treatment group showing a significant reduction in tumor volume and weight compared to the monotherapy groups.
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