Generation of Pim kinase inhibitors based on structural and post-transcriptional analysis

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The serine/threonine kinase Pim-1 plays an important role in cell cycle progression and apoptosis inhibition, resulting in prostate tumorigenesis. Therefore, Pim-1 inhibition has been expected to be an attractive target for developing new anti-cancer drugs. However, no small compounds targeting Pim-1 have progressed to clinical use because of their lack of specificity. Here we analyzed the X-ray crystal structure of Pim-1 in complex with p27^<Kip1> peptide at 1.6 A resolution. Adding eight tandem Arg residues, R8, we generated a new cell-permeable Pim-1-inhibitory p27^<Kip1> peptide that could interfere with the binding of Pim-1 to its substrates and act as an anti-cancer drug. Treatment of prostate cancer DU145 with the peptide induces G1 arrest and subsequently apoptosis in vitro. The peptide could also inhibit tumor growth in in vivo prostate cancer xenograft models.