title: 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.
authors.affiliation: Research Group of Inflammation Biology and Immunogenomics, Hungarian Academy of Sciences-Semmelweis University, Budapest, Hungary.
authors.forename: Eszter
authors.initials: E
authors.lastname: Herczenik
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Varga
authors.forename: Dániel
authors.initials: D
authors.lastname: Eros
authors.forename: Veronika
authors.initials: V
authors.lastname: Makó
authors.forename: Melinda
authors.initials: M
authors.lastname: Oroszlán
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Rugonfalvi-Kiss
authors.forename: László
authors.initials: L
authors.lastname: Romics
authors.forename: George
authors.initials: G
authors.lastname: Füst
authors.forename: György
authors.initials: G
authors.lastname: Kéri
authors.forename: László
authors.initials: L
authors.lastname: Orfi
authors.forename: László
authors.initials: L
authors.lastname: Cervenak
mesh_terms: D000970:Antineoplastic Agents / Q000302:isolation & purification* / Q000494:pharmacology; D002478:Cells, Cultured; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000302:isolation & purification* / Q000494:pharmacology; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014470:Umbilical Cord / Q000166:cytology / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries