Alofanib (RPT835) is a novel selective allosteric inhibitor of FGFR2 and has a dramatic inhibitory effect with IC50 <10 nM on FGF2-induced phoshphorylation of FRS2a in KATO III cells. Alofanib induces mainly apoptosis with cleavage of caspase 3, PARP and Bcl-2 in SKOV3 cell line. Cytotoxic effect of compound on ovarian cancer cells is low. Alofanib inhibits phosphorylation of FRS2α with the IC50 values of 7 and 9 nmol/l in cancer cells expressing different FGFR2 isoforms. In a panel of four cell lines representing several tumour types (triple-negative breast cancer,melanoma, and ovarian cancer), alofanib inhibits FGF-mediated proliferation with 50% growth inhibition (GI50) values of 16-370 nmol/l. Alofanib dose dependently inhibits the proliferation and migration of human and mouse endothelial cells (GI50: 11-58 nmol/l) compared with brivanib and bevacizumab.
In vivo, Intravenous alofanib significantly in dose-dependent manner potentiated the efficiency of the combination of paclitaxel and carboplatin. Alofanib suppresses angiogenesis in ovarian cancer mouse model. In a FGFR-driven human tumour xenograft model, oral administration of alofanib is well tolerated and results in potent antitumour activity.
| Cell Experiment | |
|---|---|
| Cell lines | SKOV3, HS478T, Mel Kor cells |
| Preparation method | Inhibited growth of SKOV3 and HS578T cells with GI50s of 0.37 and 0.21 μM. Did not potently inhibit growth of Mel Kor cells that do not contain FGFR2 (GI50>10 μM). |
| Concentrations | 0.2, 0.4, 0.8 μM |
| Incubation time | 6 hours after dosing, FGF2 is added at a concentration of 25 ng/ml |
| Animal Experiment | |
|---|---|
| Animal models | C57Bl/6 × DBA/2 F1 mice of 22-30 g |
| Formulation | vehicle (water) |
| Dosages | 10 mg/kg/d |
| Administration | Intraperitoneally, 0, 3 and 6 d |
| Molecular Weight | 413.40 |
| Formula | C19H15N3O6S |
| CAS Number | 1612888-66-0 |
| Solubility (25°C) | DMSO ≥ 30 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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