Protein kinase inhibitor-induced endothelial cell cytotoxicity and its prediction based on calculated molecular descriptors

Abstract

Protein kinase inhibitors (PKIs) as potent signal transduction therapeutic compounds represent a very rapidly expanding group of anticancer drugs. These agents may be toxic for endothelial cells, however, very few experimental data exist on the cytotoxicity of PKIs. The aim of this study was to set up an appropriate test system for endothelial cells and to assess the structure-related cytotoxic effects of a selected library of PKIs. The inhibitor library contains several lead molecules with different basic structures and a set of modified derivatives of the lead compounds. The toxicity of PKIs did not correlate directly with the structural features of the molecules. However, we successfully built up a model based on 15 calculated molecular descriptors, which is capable of predicting cytotoxicity with acceptable probability. Our results show that the cytotoxic effects of PKIs should be taken into account for optimal drug development to overcome endothelial cell-related side effects.

Keywords::

• Protein kinase inhibitor
• endothelial cells
• cytotoxicity
• molecular descriptor

Acknowledgments

Financial support was provided by the following grants: The Hungarian National Research and Development Grants (NKFP) 1/047/2001 and 1/A/005/2004 (GF, LC, GK, LO); the ATHERNET (QLG1-CT-2002-90393) grant of European Community (GF, LC); Cooperative Research Centre Grant (KKK-01/2001, MO); GVOP-3.1.1.-2004-05-0368/3.0 (GK, LO); INCA-018704 (GK, LO); and NKFP1-010/2005 (GK, LO).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.