The Pim
protein kinases play important roles in
cancer development and progression, including prostate
tumors and
hematologic malignancies. To investigate the potential role of these
enzymes as anticancer
drug targets, we have synthesized novel benzylidene-thiazolidine-2,4-diones that function as potent Pim
protein kinase inhibitors. With IC(50) values in the nanomolar range, these compounds block the ability of Pim to phosphorylate
peptides and
proteins in vitro and, when added to DU145
prostate cancer cells overexpressing Pim, inhibit the ability of this
enzyme to phosphorylate a known substrate, the
BH(3)
protein BAD. When added to
prostate cancer cell lines, including PC3, DU145, and CWR22Rv1, and human leukemic cells, MV4;11, K562, and U937 cells, these compounds induce G(1)-S cell cycle arrest and block the antiapoptotic effect of the Pim
protein kinase. The cell cycle arrest induced by these compounds is associated with an inhibition of
cyclin-dependent kinase 2 and activity and translocation of the Pim-1 substrate p27(Kip1), a
cyclin-dependent kinase 2 inhibitory
protein, to the nucleus. Furthermore, when added to leukemic cells, these compounds synergize with the
mammalian target of rapamycin inhibitor
rapamycin to decrease the phosphorylation level of the translational repressor 4E-BP1 at sites phosphorylated by
mammalian target of rapamycin. Combinations of
rapamycin and the benzylidene-thiazolidine-2,4-diones synergistically block the growth of leukemic cells. Thus, these agents represent novel Pim inhibitors and point to an important role for the Pim
protein kinases in cell cycle control in multiple types of
cancer cells.