PKI-166

PKI-166 is an ATP-competitive inhibitor of the EGF receptor (EGFR; IC₅₀ = 0.0007 µM for the intracellular kinase domain).¹ It is selective for the EGFR intracellular kinase domain over the serine/threonine kinases PKCα and Cdc2/cyclin B (IC₅₀s = >100 and 78 µM, respectively), as well as FLK, c-Met, and Tek (IC₅₀ = >1 µM for all), but does inhibit c-Src, c-Abl, VEGFR2/KDR, FLT1, and c-Kit (IC₅₀s = 0.103, 0.028, 0.327, 0.962, and 2.21 µM, respectively). PKI-166 prevents phosphorylation of EGFR induced by EGF in L3.6pl pancreatic cancer cells in a concentration-dependent manner. It enhances the cytotoxicity of gemcitabine (Item No. 11690) in L3.6pl cells and reduces tumor growth and metastasis and increases survival in an L3.6pl mouse xenograft model when administered alone at a dose of 100 mg/kg per day with additive effects on these parameters when administered in combination with gemcitabine. PKI-166 also reduces tumor growth and inhibits angiogenesis in an SN12-PM6 human renal cell carcinoma mouse orthotopic model.

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1. Bruns, C.J., Solorzano, C.C., Harbison, M.T., et al. Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer Res. 60(11), 2926-2935 (2000).