BN82002 is a potent, selective and irreversible inhibitor of CDC25 phosphatase family with IC50 values of 2.4µM, 3.9µM, 6.3µM, 5.4µM and 4.6µM for 25A, 25B2, 25B3, 25C and 25C-cat, respectively. BN82002 exhibited anti-inflammatory functions via targeting AKT2.
CDC25 dual-specificity phosphatases are essential regulators that dephosphorylate and activate cyclin-dependent kinase/cyclin complexes at key transitions of the cell cycle. CDC25 activity is currently considered to be an interesting target for the development of new antiproliferative agents. BN82002, a novel CDC25 inhibitor, inhibits in vitro the activity of CDC25C phosphatase in a concentration dose manner with an IC50 of 5.4 μM. All of the examined human tumor cell lines were sensitive to BN82002 in a concentration-dependent manner in the low micromolar range. The most sensitive was the pancreatic cancer cell line MIA PaCa-2 with an IC50 of 7.2 μM. Treatment with BN82002 at 50 μM and 100 μM for 1 hour induced an accumulation of the tyrosine 15-phosphorylated form of CDK1. The inhibition of CDK-1 dephosphorylation suggests that BN82002 efficiently down-regulates the activity of the CDC25C phosphatase toward CDK1 in cultured MIA PaCa-2 cells. In a human osteosarcoma cell line U2OS treated with 50 μM BN82002, the activity of CDC25B was inhibited by ∼60%. Collectively, these results indicate that treatment with BN82002 inhibits CDC25 phosphatase activity in cultured cells. After 24 h of treatment by 50 μM BN82002 in HeLa cells, a concentration that fully inhibits cell proliferation, the cell cycle distribution was only modestly affected with a slight decrease in S phase and an increase in cells containing both a G1 and a G2 DNA content, suggesting that the cells treated with BN82002 were arrested at various stages of the cell cycle. In athymic mice xenografted with the human pancreatic cell MIA PaCa-2, BN82002 stabilized tumor growth during the once daily × 10 days at 15 mg/kg treatment and induced a delay in the once weekly × 3 weeks at 40 mg/kg schedule[1].
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