TAK-960

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Description

TAK-960 is a novel, potent and selective PLK1 inhibitor with a minimal IC50 of 8 nM. The discovery of TAK -960 provides an interesting example of how the addition of fluorine atoms during optimization significantly alters the attributes of the leads series. TAK-960 has revealed anti-tumor activity in several tumor cell lines including those that express multidrug resistant protein 1 (MDR1). In good agreement with PLK1 prevention, TAK-960 treatment gives rise to accumulation of G2/M cells, aberrant “polo” mitosis morphology, and increases phosphorylation of histone H3 (pHH3). 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 with EC50 of 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. In animal models, oral administration of TAK-960 elevates the levels of pHH3 in a dose-dependent manner and significantly inhibits the growth of HT-29 colorectal cancer xenografts. Treatment with once-daily TAK-960 exhibits significant efficacy against multiple tumor xenografts, including an adriamycin/paclitaxel-resistant xenograft model and a disseminated leukemia model. TAK-960 has entered phase I clinical evaluation in patients with advanced cancers.

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