Varlitinib

Varlitinib (ASLAN001) is a potent, reversible, small molecule pan-EGFR inhibitor with IC₅₀s of 7, 2, 4 nM for HER1, HER2 and HER4, respectively^[1]. IC50 & Target: IC50: 7 nM (HER1), 2 nM (HER2), 4 nM (HER4)^[1] In Vitro: In cell-based assays using tumor cells that over-express EGFR (A431) or ErbB-2 (BT474), Varlitinib (ARRY-334543) potently inhibits substrate phosphorylation. Varlitinib is shown to be highly selective for EGFR/ErbB-2, and does not show any significant activity when screened against a panel of 104 kinases^[2]. In Vivo: Varlitinib treatment potently inhibits tumor growth with complete tumor regression observed at dosing of 100 mg/kg twice a day. After five days of Varlitinib treatment, phosphorylation of HER1-3, RAS/RAF/MEK/MAPK, p70S6K, S6 ribosomal, 4EBP1, Cdk-2, Cdc-2 and retinoblastoma are strongly inhibited. Varlitinib treatment results in a significant reduction in survivin and a concomittant increase in Caspase 3 cleavage products^[1]. In murine xenograft models, Varlitinib (ARRY-334543) demonstrates significant dose-related (25, 50, 100 mg/kg) tumor growth inhibition in A431-derived tumors when administered orally, twice a day, for 21 days^[2].