In vitro: Beyond ALK, IGF1R, and InsR, Brigatinib (AP26113) also potently inhibits FLT3 and ROS1 with IC50 values of 2.1 and 1.9 nM, respectively. It does not show significant activity toward c-Met or Ron up to 1 μM. Brigatinib (AP26113) overcomes the resistance of EGFR-triple-mutant and the activity depends on ATP-competitive manner with less affection to wild-type EGFR.
In vivo: Mouse PK parameters for Brigatinib (AP26113) following oral dosing (10 mg/kg): Cmax=448 ng/mL,t1/2=5.8 h. And in CD rats, after dosing at 3 mg/kg i.v, CL=0.46 L/(h·kg), t1/2=4.8 h, Vss=7.8 L/kg; Dosed at 10 mg/kg p.o, Cmax=305 ng/mL, tmax=4 h, t1/2=3.4 h， F%=52. Brigatinib (AP26113) demonstrates dose-dependent antitumor activity. Brigatinib (AP26113) demonstrates growth inhibition activity in PC9 triple-mutant xenograft model and in combination with anti-EGFR antibody to potentiate the efficacy both in vitro and in vivo as shown in first-generation EGFR-TKI-resistant patients.
Mol Cancer Ther. 2022 Jul 5;21(7):1060-1066.
HJM-561, a Potent, Selective, and Orally Bioavailable EGFR PROTAC that Overcomes Osimertinib-Resistant EGFR Triple Mutations
AP26113 (Brigatinib) purchased from AbMole
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Source | Mol Cancer Res (2015). Figure 1. AP26113 |
| Method | Western blot | |
| Cell Lines | KARPAS-299, SUP-M2 cell lines | |
| Concentrations | 0, 100, 300, and 1000 nmol/L | |
| Incubation Time | 20 nmol/L | |
| Results | In all AP26113-resistant KARPAS-derived cell lines, STAT-3 P-Tyr705 was present at higher drug doses than the one observed for parental cells and correlated with the persistent NPM-ALK phosphorylation |
| Cell Experiment | |
|---|---|
| Cell lines | H3122, H3122 CR, A549, H1299, SKBR3, H522, H460, and BT474 cells |
| Preparation method | Survival assays For 72-h drug treatments, 3000 cells were plated in replicates of six into 96-well plates. Following drug treatments, cells were incubated with CellTiter-Glo assay reagent (Promega) for 10 min and luminescence was measured using a Centro LB 960 microplate luminometer (Berthold Technologies). |
| Concentrations | 0~1µ M |
| Incubation time | 72 h |
| Animal Experiment | |
|---|---|
| Animal models | H3122 CR xenografts in athymic nude mice |
| Formulation | saline |
| Dosages | 50 mg/kg/day for 17 days |
| Administration | oral gavage |
| Molecular Weight | 584.09 |
| Formula | C29H39ClN7O2P |
| CAS Number | 1197953-54-0 |
| Solubility (25°C) | Ethanol 6 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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