ARRY-334543, A potent, orally active small molecule inhibitor of EGFR and ErbB-2

3399 The growth factor receptor tyrosine kinases EGFR (ErbB-1) and ErbB-2 (HER-2/neu) play a major role in controlling cell growth, differentiation and survival. These two receptor tyrosine kinases are often over-expressed and/or abnormally active in a wide variety of tumor types. Currently several drugs have been developed that selectively inhibit either EGFR or ErbB-2. Despite some clinical success with the selective agents, data suggest concomitant inhibition of both kinases maybe a more efficacious approach for the treatment of tumors. At the present time, there are no approved therapeutic agents that target both EGFR and ErbB-2, although several compounds are currently under investigation. In a series of experiments we demonstrate that ARRY-334543 is a novel, potent, orally active dual inhibitor of EGFR and ErbB-2. The compound is a reversible ATP-competitive inhibitor with nanomolar potency against both kinases in vitro. In cell-based assays using tumor cells that over-express EGFR (A431) or ErbB-2 (BT474), ARRY-334543 potently inhibited substrate phosphorylation. ARRY-334543 was shown to be highly selective for EGFR/ErbB-2, and did not show any significant activity when screened against a panel of 104 kinases. In murine xenograft models ARRY-334543 demonstrated significant dose-related (25, 50, 100 mg/kg) tumor growth inhibition in A431-derived tumors when administered orally, BID, for 21 days. Based on potency, selectivity and efficacy data, the compound is currently in development as an anti-cancer agent.