Inhibition of mitogen-activated protein kinase (MAPK) and cyclin-dependent kinase 2 (Cdk2) by platinum(II) phenanthrolin
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ORIGINAL ARTICLE
Inhibition of mitogen-activated protein kinase (MAPK) and cyclin-dependent kinase 2 (Cdk2) by platinum(II) phenanthroline complexes Emma S. Child & Savvas N. Georgiades & Kirsten N. Rose & Verity S. Stafford & Chirag B. K. Patel & Joachim H. G. Steinke & David J. Mann & Ramon Vilar
Received: 30 July 2010 / Accepted: 9 February 2011 / Published online: 26 February 2011 # Springer-Verlag 2011
Abstract Inhibition of protein kinases in the fight against disease remains a constant challenge for medicinal chemists, who have screened multitudes of predominantly planar organic scaffolds, natural and synthetic, to identify potent— albeit not always selective—kinase inhibitors. Herein, in an effort to investigate the potential biological utility of metalbased compounds as inhibitors against the cancer-relevant targets mitogen-activated protein kinase and cyclin-dependent kinase 2, we explore various parameters in planar platinum(II) complexes with substituted phenanthroline ligands and aliphatic diamine chelate co-ligands, to identify combinations that yield promising inhibitory activity. The individual ligands’ steric requirements as well as their pattern of hydrogen bond donors/acceptors appear to alter inhibitory potency when modulated. Keywords Platinum . Kinase . Cdk . Bioinorganic . MAPK . ERK . Inhibitor
Electronic supplementary material The online version of this article (doi:10.1007/s12154-011-0059-5) contains supplementary material, which is available to authorized users. E. S. Child : D. J. Mann (*) Division of Cell and Molecular Biology, Imperial College London, South Kensington, London SW7 2AZ, UK e-mail: [email protected] S. N. Georgiades : K. N. Rose : V. S. Stafford : C. B. K. Patel : J. H. G. Steinke : R. Vilar (*) Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK e-mail: [email protected]
Introduction Many fundamental biological events are regulated by protein phosphorylation. Such phosphorylation is catalysed by members of the protein kinase family and these enzymes are often deregulated in disease. Consequently, there is much interest in developing inhibitors for individual protein kinases for therapeutic purposes. Most protein kinase inhibitors bind to the enzyme at the ATP binding site. Since many protein kinases share similar structurally conserved binding sites, this can lead to undesired offtarget effects [1, 2]. This approach has been successfully employed to develop a large number of kinase inhibitors (see Fig. 1 for selected examples). Many kinase inhibitors feature a planar aromatic core that occupies the same space in the protein kinase ATP binding site normally filled by adenine. Specificity is determined largely by addition of hydrogen bond donor/acceptor groups and flexible substituents to these cores (see Fig. 1). While organic compounds have been extensively studied in this context, far less is known about the therapeutic properties of metal complexes. The structural versatility of metal centres provides a unique opportunity
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