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 due to their lack of specificity. The PIM Kinase inhibitor VIII, R8-T198wt product is part of the Merck brand. PIM Kinase inhibitor VIII, R8-T198wt's primary application is to inhibit its target molecule, but it may also be adjusted to fit corresponding scientific methods.
R8-T198wt peptide is a new cell-permeable Pim-1 inhibitory that could interfere with the binding of Pim-1 to its substrates and act as an anti-cancer drug. The peptide could bind to Pim-1 and inhibit phosphorylation of endogenous p27Kip1 and Bad by Pim-1. Treatment of prostate cancer with the peptide induces G1 arrest and subsequently apoptosis in vitro. However, the peptide showed almost no growth inhibitory or apoptosis-inducing effects in normal cells. The peptide could inhibit tumor growth in vivo prostate cancer xenograft models. Moreover, the peptide treatment could overcome resistance to taxol, one of the first line chemotherapeutic agents for prostate cancer, and a combination of the peptide with taxol synergistically inhibited prostate cancer growth in vivo. These results indicate that a Pim-1 inhibitory R8-T198wt peptide could be developed as an anti-cancer drug against prostate cancer.
The carboxyl-terminal Thr198 residue in human p27Kip1 was phosphorylated by Pim-1. Phosphorylation was inhibited by the R8-T198wt peptide in a dose-dependent manner. In contrast, the R8-T198mu peptide could hardly suppress Pim-1-mediated p27Kip1 phosphorylation. Thr198 phosphorylation by Pim-1 could not be detected when the cells were cotransfected with Pim-1 and p27Kip1 T198A mutant. These results indicate that the R8-T198wt peptide could inhibit p27Kip1 phosphorylation by Pim-1 in cells. The inhibition was due to the blocking of the binding between Pim-1 and p27Kip1. The R8-T198wt peptide inhibited the growth of prostate cancer cells more than that of normal prostate cells.
Pharmacokinetics and metabolism
Mice were treated with vehicle or R8-T198wt peptide and taxol alone or taxol and R8-T198wt peptide. Tumor size was significantly smaller in the group treated with the R8-T198wt peptide compared with the vehicle-treated group. No toxic death or significant body weight change was observed throughout these experiments. Co-treatment with taxol and R8-T198wt peptide showed a marked inhibitory effect on the development of DU145 xenografts compared with taxol alone, with a reduction of 52 and 61% tumor volume. Although toxic death was not observed in this experiment, a slight decrease in body weight was observed in the R8-T198wt peptide and taxol group. These results suggest that the R8-T198wt peptide has in vivo anti-tumor activity and can increase sensitivity to taxol with minimal toxicity in mice.
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