Varlitinib

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.