RKI-1447 is a potent and selective ROCK inhibitor with significant anti-invasive and antitumor activities. RKI-1447 binds the ATP binding site through interactions with the hinge region and the DFG motif. RKI-1447 inhibited migration, invasion and anchorage-independent tumor growth of breast cancer cells. RKI-1447 was also highly selective at inhibiting ROCK-mediated cytoskeleton re-organization (actin stress fiber formation) following LPA stimulation, but does not affect PAK-meditated lamellipodia and filopodia formation following PDGF and Bradykinin stimulation, respectively. RKI-1447 suppressed phosphorylation of the ROCK substrates MLC-2 and MYPT-1 in human cancer cells, but had no effect on the phosphorylation levels of the AKT, MEK and S6 kinase at concentrations as high as 10 μmol/L. Finally, RKI-1447 was highly effective at inhibiting the outgrowth of mammary tumors in a transgenic mouse model.
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Source | Neoplasia (2018). Figure 7. RKI-1447 |
| Method | 3D spheroid invasion assays | |
| Cell Lines | MSC-4H-FC cells | |
| Concentrations | 10 μM | |
| Incubation Time | 24 h | |
| Results | Importantly, concentrations of RKI-1447 as low as 0.5 μM were able to completely abolish the invasion of MSC-4H-FC 3D spheroids and to significantly reduce cell extravasation out of the CAM vasculature without having any relevant effect on cell proliferation. |
| Molecular Weight | 326.37 |
| Formula | C16H14N4O2S |
| CAS Number | 1342278-01-6 |
| Solubility (25°C) | DMSO 55 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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