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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Source | BMC Cancer (2018). Figure 2. TAK-960 |
| Method | Clonogenic analysis | |
| 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 |
| Molecular Weight | 561.6 |
| Formula | C27H34F3N7O3 |
| CAS Number | 1137868-52-0 |
| Solubility (25°C) | DMSO 32 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
[2] Chetasi Talati, et al. Polo-like kinase inhibitors in hematologic malignancies
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