title: Factors influencing the inhibition of protein kinases.
abstract: The protein kinase field is a very active research area in the pharmaceutical industry and many activities are ongoing to identify inhibitors of these proteins. The design of new chemical entities with improved pharmacological properties requires a deeper understanding of the factors that modulate inhibitor-kinase interactions. In this report, we studied the effect of two of these factors--the magnesium ion cofactor and the protein substrate--on inhibitors of the type I insulin-like growth factor receptor. Our results show that the concentration of magnesium ion influences the potency of adenosine triphosphate (ATP) competitive inhibitors, suggesting an explanation for the observation that such compounds retain their nanomolar potency in cells despite the presence of millimolar levels of ATP. We also showed that the peptidic substrate affects the potency of these inhibitors in a different manner, suggesting that the influence of this substrate on compound potency should be taken into consideration during drug discovery.
authors.affiliation: Druggability-Enzymology-Profiling Unit, Oncology Research, Novartis Institutes of BioMedical Research, Basel, Switzerland.
authors.forename: Marielle
authors.initials: M
authors.lastname: Brockhoff
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Hau
authors.forename: Patrizia
authors.initials: P
authors.lastname: Fontana
authors.forename: Catherine
authors.initials: C
authors.lastname: Zimmermann
authors.forename: Alain De
authors.initials: AD
authors.lastname: Pover
authors.forename: Dirk
authors.initials: D
authors.lastname: Erdmann
authors.forename: Patrick
authors.initials: P
authors.lastname: Chène
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008274:Magnesium / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D011487:Protein Conformation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry*; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D019311:Staurosporine / Q000494:pharmacology; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; C501177:NVP-AEW541; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D017526:Receptor, IGF Type 1; D019311:Staurosporine; D008274:Magnesium