In vitro: In cells, inhibition of FGFR2 auto-phosphorylation and other proteins downstream in the FGFR pathway (FRS2α, AKT, ERK) was evident by the response to ARQ 087 treatment. Cell proliferation studies demonstrated ARQ 087 has anti-proliferative activity in cell lines driven by FGFR dysregulation, including amplifications, fusions, and mutations. Cell cycle studies in cell lines with high levels of FGFR2 protein showed a positive relationship between ARQ 087 induced G1 cell cycle arrest and subsequent induction of apoptosis.
In vivo: ARQ 087 was effective at inhibiting tumor growth in vivo in FGFR2 altered, SNU-16 and NCI-H716, xenograft tumor models with gene amplifications and fusions. ARQ 087 is currently being studied in a phase 1/2 clinical trial that includes a sub cohort for intrahepatic cholangiocarcinoma patients with confirmed FGFR2 gene fusions.
| Cell Experiment | |
|---|---|
| Cell lines | COS-1 cells |
| Preparation method | Cells were seeded at 3000–5000 cells per well with 130 μL media in 96-well tissue culture treated plates. The cells were incubated overnight and subsequently treated with 3-fold serial dilutions of ARQ 087 starting at 100 μM. The cells were returned to a 37°C humidified incubator for 72 hours. |
| Concentrations | 100 μM |
| Incubation time | 72 h |
| Animal Experiment | |
|---|---|
| Animal models | female NCr nu/nu mice (SNU-16) or CB17 SCID mice (NCI-H716) |
| Formulation | DMA: cremophor EL: propylene glycol: 0.2 M acetate buffer, pH 5 (10:10:30:50) |
| Dosages | 10 mL/kg or 0.1 mL/10 g |
| Administration | oral |
| Molecular Weight | 468.57 |
| Formula | C29H29FN4O |
| CAS Number | 1234356-69-4 |
| Solubility (25°C) | DMSO 84 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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