AZD-0364 is a potent and selective oral inhibitor of ERK1/2 which are ubiquitously expressed MAPK kinases that participate in the RAS- RAF- MEK- ERK signalling cascade in the regulation of cell cycle progression, cell proliferation, survival, metab. and transcription. AZD-0364 can inhibit the growth of a panel of cancer cell lines (A549, H2122, H2009, and Calu6 cell lines) with KRAS mutations as a monotherapy.
In vivo, in the A549 xenograft model, Selumetinib is dosed twice daily (BiD) 8 hours apart and AZD-0364 ethanesulfonic acid is dosed once daily (QD) 4 hours after the first Selumetinib dose. Both compounds are dosed continuously for 3 weeks. Both vehicles are dosed in the vehicle group. Both Selumetinib and AZD-0364 ethanesulfonic acid reduce tumor growth relative to vehicle only control.
| Cell Experiment | |
|---|---|
| Cell lines | KRAS-mutant Non-Small Cell Lung Cancer (NSCLC) A549, H2122, H2009, and Calu6 cell lines |
| Preparation method | KRAS-mutant Non-Small Cell Lung Cancer (NSCLC) A549, H2122, H2009, and Calu6 cell lines are seeded in 384-well black, clear bottomed plates, cultured for 18-24 hours and treated with increasing concentrations of AZD-0364 (7.143 nM, 61 nM, 357 nM, 2.143 μM and 10 μM) and Selumetinib (0-10 μM) in a 6×6 dosing matrix. Cells are seeded at a concentration such that cells in untreated wells are approximately 80% confluent at the end of the assay. After 3 days of treatment, live cell number is determined using a Sytox Green endpoint. |
| Concentrations | 7.143 nM, 61 nM, 357 nM, 2.143 μM and 10 μM |
| Incubation time | 3 days |
| Animal Experiment | |
|---|---|
| Animal models | Female nude mice implanted subcutaneously (s.c.) on the left flank, with 5×106 A549 cells |
| Formulation | |
| Dosages | 25 mg/kg QD (four hours after first Selumetinib dose) |
| Administration | peroral route |
| Molecular Weight | 494.50 |
| Formula | C24H24F2N8O2 |
| CAS Number | 2097416-76-5 |
| 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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