oa Editorial [Hot Topic: Current Research on Protein Kinases (Guest Editors: Jari Yli-Kauhaluoma & Raimo K. Tuominen)]

The present issue of CTMC aims at updating biological information of some important protein kinases (PKs) as basis for drug discovery, and frontline design and synthesis of novel compounds and biologics. Since discovery of staurosporine, an ATP-competitive non-selective kinase inhibitor, research on PK inhibitors has increased exponentially. A beautiful fruit of these efforts is imanitib, a small molecule PK inhibitor for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. Imatinib is an inhibitor of the tyrosine kinases BCR-ABL, c-KIT, and the platelet-derived growth factor receptor (PDGF) TK. Human genome encodes more than 500 PKs [1]. Protein kinases catalyse protein phosphorylation, an important means by which cell functions are regulated [2]. Aberrant expression of PKs, usually producing overactivity of a PK, leads to disease processes, e.g. the development of cancer. PKs are also major players in the signalling of cytokines and other mediators of inflammation. PK structures in non-mammalian cells such as in certain parasites (e.g. Leishmania sp.) differ from mammalian ones [3] and they are therefore most interesting targets for PK inhibitors. Degenerative brain diseases such as Alzheimer’s disease may in the future be therapeutic target for drugs acting on PKs. Thus, drugs affecting PKs (or more widely protein phosphorylation) may be of great importance in future treatment strategies of a large variety of diseases. Biologics, such as trastuzumab, are effective drugs acting on receptor tyrosine kinases (RTKs). However, most of the PKs are intracellular and biologicals are not able to enter the cell. Therefore, most of the effort has been used to develop small molecules that would penetrate the cell membranes and affect the intracellular PKs including intracellular domains of RTKs. Virtually all PK-inhibitors in clinical use today are targeted on the ATP binding site in the catalytic domain of the PKs. It is surprising that many of the drugs show rather good selectivity, although the ATP binding site in PKs is rather similar. Also allosteric inhibitors of PKs have been discovered that apparently is a way to overcome the structural similarity of the ATPbinding pocket [4]. Other possibilities to modify PK activity include regulatory domains of certain kinases such as PKA and PKC. PKCregulatory domain is unique to PKC and is not found in other PKs. The C1-domain of PKC is the binding site of DAG, the physiological activator of the enzyme. The C1-domain of various PKC-isoenzymes is an attractive drug-target, since the drugs would probably have specificity for PKCs over other kinases and it would also be possible to discover PKC-isozyme-selective inhibitors. The catalytic domain of various PKs is highly conserved, especially the ATP binding site. On the other hand, the region surrounding the sensu stricto ATP binding site is quite variable from one kinase to another and can be exploited for the specific binding of ligands that will act as selective inhibitors competing with ATP [5]. Anchoring proteins, such as the receptors for activated C-kinase, RACK1 and RACK2, bind to PKC?? and translocate it to the site of catalytic activity [6]. Several peptides inhibit the binding of PKCε to RACK1 or RACK2 [7]. The PKCε-derived octapeptide HDAPIGYD has been shown to be a PKCε agonist and prevents the heart from ischemic damage [8]. It is obvious that we need compounds that are rather selective to one or several kinases. Opposite to a major pharmacological principle, protein kinase inhibitors may not necessarily need to be specific to a single PK but, rather, could inhibit several “correct” kinases simultaneously. This is of course a major challenge to a rational and structure-based drug discovery and, indeed, there is an increasing need for better in vitro and in vivo models of diseases to test such compounds.