Rational Design of a Potent Pan-Pim Kinases Inhibitor with a Rhodanine-Benzoimidazole Structure.

BACKGROUND/AIM: The serine/threonine Pim kinases are overexpressed in various types of solid carcinomas and hematological malignancies, and contribute to regulating cell-cycle progression and cell survival. The aim of this study was to discover a novel pan-Pim kinases inhibitor with potent anti-proliferative activities against cancer cell lines.

MATERIALS AND METHODS: We screened a panel of small molecule compounds for their ability to inhibit Pim-1 kinase activity, and the hit compound was optimized using the docking analysis to Pim-1. We evaluated kinase-inhibition activities of the rationally-designed compound against Pim-1, 2, 3 and another five kinases. Furthermore, in order to characterize the cellular activities, both solid and hematological cancer cell lines treated with the compound were subjected to anti-proliferative assay, western blotting, FACS and apoptosis assays.

RESULTS: We discovered a pan-Pim kinases inhibitor, compound 1, with a rhodanine-benzylidene structure via Pim-1 inhibitor screening. Using docking analysis of compound 1 and Pim-1, we optimized it and found a potent- and selective-Pim kinases inhibitor, compound 2, with a rhodanine-benzoimidazole structure. Compound 2 inhibited Pim-1, 2, 3 with IC50 values of 16, 13, and 6.4 nM, respectively, and suppressed proliferation of solid and hematological cancer cell lines at submicromolar concentrations. In both types of cell lines, compound 2 inhibited phosphorylation of Pim signaling substrates and cell-cycle progression and induced apoptosis.

CONCLUSION: We identified a pan-Pim kinases inhibitor, compound 2, with a rhodanine-benzoimidazole structure. Our data suggest that compound 2 can serve as a lead to novel anticancer agents, effective in the treatment of both solid carcinomas and hematological malignancies.