AZ304 is a potent dual BRAF inhibitor targeting the kinase domains of wild type BRAF, V600E mutant BRAF with IC50 values of 79 nM and 38 nM respectively. AZ304 potently reduces ERK phosphorylation (p-ERK), with a mean EC50 of 65 nM in the V600E mutant BRAF containing melanoma cell line A375, and EC50s of 52 nM, 60 nM in the wild type BRAF melanoma cell line SK-MEL-31 with and without EGF. AZ304 dose-dependently inhibits the growth of RKO, HT-29, DiFi, and Caco-2, with GI50s of 4.539 μM, 3.896 μM, 4.987 μM, 1.763 μM (48 hours) and 0.5032 μM, 0.3887 μM, 0.6354 μM, 0.3772 μM (72 hours), respectively.
| Cell Experiment | |
|---|---|
| Cell lines | RKO, HT-29, DiFi, Caco-2 cells |
| Preparation method | Anti-proliferative activity of AZ304 and Cetuximab in CRC cell lines with different BRAF mutation status. Two V600E mutant BRAF cell lines (RKO, HT-29) and two wild-type BRAF cell lines (DiFi, Caco-2) were treated with DMSO or increasing concentrations of AZ304 (0, 0.1, 1, 10, 100 μM), for 48 h and 72 h. Viable cells were determined by MTT assay. |
| Concentrations | 0, 0.1, 1, 10, 100 μM |
| Incubation time | 48, 72 hours |
| Animal Experiment | |
|---|---|
| Animal models | Female 4-6 weeks old athymic BALB/c nude mice inoculated with RKO/Caco-2 cells |
| Formulation | dissolved in 0.5% HPMC |
| Dosages | 10 mg/kg twice daily |
| Administration | oral gavage |
| Molecular Weight | 451.52 |
| Formula | C27H25N5O2 |
| CAS Number | 942507-42-8 |
| 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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