TAK-632 is a selective kinase inhibitor targeting pan-RAF inhibition. TAK-632 inhibited phosphorylation of MEK (pMEK) in melanoma A375 cells (BRAFV600E) with an IC50 value of 12 nM. TAK-632 suppresses RAF activity in BRAF wild-type cells with minimal RAF paradoxical activation. TAK-632 induces RAF dimerization but inhibits the kinase activity of the RAF dimer, probably because of its slow dissociation from RAF. TAK-632 demonstrates potent antiproliferative effects both on NRAS-mutated melanoma cells and BRAF-mutated melanoma cells with acquired resistance to BRAF inhibitors through NRAS mutation or BRAF truncation.
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Source | Cancer Res (2013). Figure 1. TAK-632 |
| Method | Western blot analysis | |
| Cell Lines | A431, CsFb, and HeLa cells | |
| Concentrations | 0-5000 nmol/L | |
| Incubation Time | 2 h | |
| Results | MEK and ERK phosphorylation was modestly induced at low TAK-632 concentrations but inhibited at higher concentrations in BRAF wild-type cells |
| Molecular Weight | 554.52 |
| Formula | C27H18F4N4O3S |
| CAS Number | 1228591-30-7 |
| Solubility (25°C) | DMSO 90 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.
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