TAK-960

TAK-960 has shown activity in several tumor cell lines including those that express multidrug resistant protein 1 (MDR1). ^[1] Consistent with PLK1 inhibition, TAK-960 treatment gives rise to accumulation of G2/M cells, aberrant "polo" mitosis morphology, and increases phosphorylation of histone H3 (pHH3). ^[1] TAK-960 inhibits proliferation of multiple cancer cell lines, with mean EC50 values ranging from 8.4 to 46.9 nM, but not in non-dividing normal cells (EC50 >1,000 nM). The mutation status of TP53 or KRAS and MDR1 expression does not correlate with the potency of TAK-960 in the cell lines tested. ^[1]

Cells are seeded into 96-well plates at 3-30 × 10³ cells/well in appropriate medium plus 10% fetal calf serum (FCS). After 24 hours, cells are treated with serial dilutions of TAK-960, and 72 hours later, the number of viable cells is assessed using the CellTiter-Glo Assay. Calculation of EC50 values and statistical analysis are done.

In animal models, oral administration of TAK-960 increases pHH3 in a dose-dependent manner and significantly inhibits the growth of HT-29 colorectal cancer xenografts. ^[1] Treatment with once-daily TAK-960 exhibits significant efficacy against multiple tumor xenografts, including an Doxorubicin-resistant xenograft model and a disseminated leukemia model. ^[1]