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.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Source||BMC Cancer (2018). Figure 2. TAK-960|
|Cell Lines||CRC cell lines|
|Concentrations||0.1, 0.5, 1 and 2 μM|
|Incubation Time||72 h|
|Results||As compared to the untreated control, TAK-960 treatment of CRC cell lines HCT116, WIDR, DLD1 and COLO678 decreased colony formation, dose dependently (p < 0.05) with little to no visible colonies in doses of TAK-960 greater than 10 nM|
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