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.
|Animal models||Athymic Ncr:Nu/Nu|
|Administration||Administered via p.o.|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.
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