ARRY334543 is a selective and potent kinase ErbB-1 and ErbB-2 inhibitor with IC50 of 7 and 2 nM, respectively. The Ki of ARRY334543 is 1 nM. ARRY334543 behaves as a reversible ATP-competitive inhibitor with nanomolar potency both in vitro and in cell-based proliferation assays using A431 and BT-474 cells. ARRY334543 is an AKT pathway inhibitor in cells that contains active ErbB-2 receptors. ARRY334543 suppresses ErbB-2 and ErbB-1 phosphorylation in human cancer cells, such as BT-474 with an IC50 of 43 nM and A431 with an IC50 of 36 nM that overexpress ErbB-2 and ErbB-1, respectively. When dosed orally, ARRY334543 dose-dpendently inhibits growth of human tumor xenografts that overexpress ErbB-1 (A431) or ErbB-2 (MDA-MB-453). ARRY334543 demonstrates significant dose related tumor growth prevention when administered orally, BID, for 21 days. ARRY334543 has very good PK/ADME properties and has revealed excellent activity in numerous mouse tumor xenograft models including epidermoid (A431), breast (BT-474, MDA-MB-453), non-small cell lung (H1650, A549, 292), colorectal (Lovo, HT-29) and gastric (N87) carcinoma models. In the BT-474 model, ARRY334543 demonstrates significant dose-related tumor growth inhibition by 69% at 100 mg/kg/d and by 98% at 200 mg/kg/d. Excellent single agent activity for ARRY334543 in the SK-OV-3 ovarian carcinoma xenograft model as well as additive activity to trastuzumab in SK-OV-3, BT-474 and NCI-N87 models has been demonstrated. ARRY334543 exhibits excellent additive activity and tolerability with docetaxel. ARRY334543 is carried out in a phase II clinical trial in the treatment of advanced cancer and pancreatic cancer.
| Cell Experiment | |
|---|---|
| Cell lines | |
| Preparation method | |
| Concentrations | |
| Incubation time | |
| Animal Experiment | |
|---|---|
| Animal models | Athymic Ncr:Nu/Nu |
| Formulation | |
| Dosages | 200 mg/kg/d |
| Administration | Administered via p.o. |
| Molecular Weight | 466.94 |
| Formula | C22H19ClN6O2S |
| CAS Number | 845272-21-1 |
| Solubility (25°C) | DMSO |
| 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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