Phenyl maleiimide deivatives, a new class of phosphatase inhibitors that are active against hepatoma cells in vitro

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We have synthesized a new class of phenyl maleiimide (PM) compounds, which are potent growth inhibitors of Hep 3B hepatoma cells in vitro, with IC50 ranging from 700 nM to 7 μM. Among these, PM-20 was the most potent (IC50 =700 nM). Two other derivatives (PM-26 and PM-38) did not inhibit Hep 3B growth even at 10 μM. Interestingly, PM-20 inhibited growth of primary rat hepatocytes at a 20 fold higher dose (IC50 =15 μM), which suggests that the new compounds may have a reasonable therapeutic index. PM-20 and the other potent derivatives induced tyrosine phosphorylation of EGFR and ERK1/2, whereas PM-26 and PM-38 did not. Inhibition of ERK1/2 phosphorylation by the MEK1/2 inhibitor U0126, antagonized the growth inhibitory effect of PM-20. Cell cycle analysis revealed a block, mainly in the G1 phase of the cell cycle and resulted in upregulation of tyrosine phosphorylation of cyclin dependent kinases Cdk1, 2 and 4. This suggests that the mechanism(s) of growth inhibition by this class of compound likely involve ERK1/2 phosphorylation and inhibition of tyrosine phosphatases that normally regulate dephosphorylation of the inhibitory phospho-tyrosine of Cdk1, 2 and 4.