Pelitinib

Pelitinib (EKB-569;WAY-EKB 569) is an irreversible inhibitor of EGFR with an IC₅₀ of 38.5 nM; also slightly inhibits Src, MEK/ERK and ErbB2 with IC₅₀s of 282, 800, and 1255 nM, respectively. IC50 & Target: IC50: 38.5 nM (EGFR), 282 nM (Src), 800 nM (MEK/ERK), 1255 nM (ErbB2)^[1] In Vitro: Pelitini has much greater inhibitory activity against the EGFR kinase than against Src, MEK/ERK, Cdk4, c-Met, Raf and ErbB2, for example, the IC₅₀ for EGFR is 32-fold lower than the IC₅₀ for the closely related ErbB2. Pelitinib results in a dramatic reduction in EGFR phosphorylation but no change in the total amount of EGFR protein. It requires at least 10-fold more drug to equivalently inhibit ErbB2 phosphorylation in similar assays, and EKB-569 does not block phosphorylation of another receptor tyrosine kinase (c-Met) assessed in the same manner^[1]. EKB-569 is a potent inhibitor of proliferation in NHEK, A431, and MDA-468 cells (IC₅₀=61, 125, and 260 nM, respectively) but not MCF-7 cells (IC₅₀=3600 nM). EKB-569 is also a potent inhibitor of EGF-induced phosphorylated EGF-R (pEGF-R) in A431 and NHEK cells (IC₅₀=20-80 nM)^[1]. In Vivo: A single oral dose of 10 mg/kg EKB-569 inhibits EGFR phosphorylation in A431 xenografts within 60 minutes. Twenty-four hours later, EGFR activity is still inhibited by over 50% by this single oral dose. The half-life of EKB-569 in mouse plasma is about 2 hours^[1].