A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and In vitro anti‐proliferative as well as In vivo anti‐tumor activity

Abstract

Analogues of staurosporine were synthesized and their ability to inhibit protein kinases was examined. Staurosporine is a potent but non-selective inhibitor of in vitro protein kinase C (PKC) activity (IC₅₀ 6.0 _nm). The derivative CGP 41 251 had reduced PKC activity with an IC₅₀ of 50 nm but showed a high degree of selectivity when assayed for inhibition of cyclic AMP-dependent protein kinase (IC₅₀, 2.4 μm). 56 kinase (IC₅₀ 5.0 μm). and tyrosine-kinase-specific activity of epidermal growth factor receptor (IC₅₀ 3.0 μm). Staurosporine and CGP 41 251 exerted growth inhibition in the human bladder carcinoma line T-24, human promyelocytic leukemia line HL-60 and bovine corneal endothelial cells at concentrations which correlated well with in vitro PKC inhibition. In addition, both compounds inhibited the release of H₂O₂ from human monocytes pre-treated with 12-O-tetradecanoyl-phorbol-13-acetate at non-toxic concentrations. In vivo anti-tumor activity was examined in T-24 human bladder carcinoma xenografts in athymic nude mice. Tumor growth inhibition tests revealed significant anti-tumor activity (2_p < 0.001) at 1/10 of the maximum tolerated doses for both compounds. By contrast, a closely related derivative of staurosporine (CGP 42 700) was inactive at concentrations of over 100 μm in all in vitro enzyme and anti-proliferative assays as well as in animal tumor models. Our data suggest an association between PKC inhibition and anti-proliferative and anti-tumor activity.