TAK-960 is a potent, selective, ATP-competitive, orally available inhibitor of polo-like kinase 1 (PLK1) with IC50 of 1.6 nM in TR-FRET assays. TAK-960 inhibits full-length PLK1 protein with IC50 of 0.8 nM, relatively inhibits PLK2 and PLK3 with IC50 of 16.9 and 50.2 nM, weakly inhibits FAK, MLCK, and FES kinases against a panel of 288 kinases. TAK-960 (10-30 nM) induces accumulation of aberrant mitotic cells in HT-29 cells. TAK-960 inhibits proliferation of human cancer cell lines regardless of TP53 and KRAS mutation and MDR1 expression status. TAK-960 treatment caused accumulation of G2–M cells, aberrant polo mitosis morphology, and increased phosphorylation of histone H3 (pHH3) in vitro and in vivo. TAK-960 inhibits proliferation of multiple cancer cell lines, with mean EC50 values ranging from 8.4 to 46.9 nM, but not in nondividing normal cells. TAK-960 significantly inhibited the growth of HT-29 colorectal cancer xenografts, exhibited significant efficacy against multiple tumor xenografts, including an adriamycin/paclitaxel-resistant xenograft model and a disseminated leukemia model.
