BBAPAP-39627; No. of pages: 2; 4C: Biochimica et Biophysica Acta xxx (2015) xxx–xxx

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This special issue of BBA (Proteins and Proteomics) comprises the extended texts of most of the invited lectures, largely in the form of reviews of the respective fields, presented at the 8th International Conference on Inhibitors of Protein Kinases (IPK ’2014), including Insights into Protein Kinases, held in Warsaw, September 21–25, 2014. Reversible protein phosphorylation, long recognized as the key pathway for regulation of protein functions in living cells, is involved in the switching of cellular activities from one state to another (signal transduction), in this way regulating basic cellular processes, such as metabolism, gene expression, cellular proliferation, and differentiation. It is the major mechanism whereby cells respond to extracellular signals, such as hormones and growth factors, and controls all events in the various stages of the cell cycle, as well as the response of a cell to environmental and nutritional stresses. Phosphorylation of proteins, catalyzed by protein kinases, is simultaneously regulated via dephosphorylation by protein phosphatases. These exquisitely coordinated activities are a reflection of the universal and versatile roles of phosphate esters and anhydrides in all living systems, comprehensively reviewed some years ago by Frank Westheimer, under the title “Why Nature chose Phosphates?” [Science 235, 1173–1178, 1987]. Given the key role of protein kinases (and protein phosphatases) in signal transduction, it is not surprising that early on this stimulated searches for inhibitors of these enzymes. To date more than 500 genes encoding protein kinases have been identified in, and account for, 2% of the human genome. In a striking contrast to other enzyme systems, it would appear to be a formidable task to design potent and specific inhibitors for a given kinase or class of kinases. Nonetheless, and notwithstanding that all kinases share a relatively common fold, there are subtle differences in the unique conformations of the catalytic pockets (flexibility and induced fit), in the local and distal docking sites between kinase and substrate, and in the charge and hydrophobicity of surface residues, all of which can play a role in determining substrate selectivity to maintain the specificity of signaling pathways. Many selective inhibitors of individual kinases from various sources have been developed and characterized, most recently by screening against large panels of kinases, as many as 400 in one recent study, hence embracing almost 80% of the human kinome. Detailed surveys of the reported properties of many of these suggest that it would be more appropriate to refer to their degree of “selectivity”, rather than “specificity”. One such study of kinase inhibitor selectivity [Karaman et al., Nature Biotechnol 26, 127–132,

2008] presented the interactions (association constants K) of 38 known kinase inhibitors across a panel of over 300 kinases, and introduced the concept of a selectivity score, S, for each inhibitor. Nonetheless, inhibitors of protein kinases are currently widely and successfully employed in studies on delineation of signaling pathways. Dysfunctions of protein kinases (and phosphatases) are associated with numerous pathological states, ranging from diabetes, through inflammatory diseases, to cancer. It is, consequently, not surprising that the pharmaceutical and biotechnology sectors are amongst the most active participants in the search for protein kinase inhibitors, primarily with an eye to their potential therapeutic applications. It has been estimated that, of the protein targets under investigation by the pharmaceutical and biotechnology sectors for therapeutic purposes, more than 40% are devoted to protein and lipid kinases. Starting with Glivec (STI-571, Imatinib, Glivec) in 2001, there are currently more than 10 FDA-approved kinase inhibitors in clinical use. More than 50 are in various stages of clinical development, and many more in preclinical trials. Bearing in mind the pivotal role of protein kinase CK2 in health and disease, especially in cancer, where its level is inordinately high, the present meeting included three lectures on this topic, as well as several posters. The discovery, in the late 1990s, of the first low-molecular-weight, cell-permeable, ATP-competitive, and relatively selective, CK2 inhibitors, with Ki values in micromolar range and lower (4,5,6,7-tetrahalogeno benzotriazoles and benzimidazoles) stimulated intense activity in this field, leading to new inhibitors, with enhanced selectivities, and Ki values extending to the nanomolar range. Amongst others, various aspects of molecular pharmacology, 6including in silico drug design, are represented. In extension of previous meetings, the present one included lectures and posters on the kinases of pathogenic agents. Since these share only limited sequence homology with their eukaryotic (host) counterparts, they are exceptionally attractive targets. It is pertinent to note that infectious agents are known as causative factors for at least 20% of the global incidence of human cancers [H. zur Hausen, Nobel lecture, 2008; see Virology 392, 1–10, 2009]. In addition to its international character, this meeting included participants representing specialists from a broad range of disciplines, embracing both academia and the biotechnology sector, thus ensuring close interplay, and stimulating exchanges between those engaged in fundamental research and those actively involved in clinical applications. 1570-9639/© 2015 Published by Elsevier B.V.

Please cite this article as: D. Shugar, et al., Preface, Biochim. Biophys. Acta (2015),



David Shugar, during the course of graduate studies at the Faculty of Physics, McGill University, Montreal, 1937–1940, assisted the University Medical Faculty in the construction and application of an ultracentrifuge to studies of proteins. Although he graduated with a PhD in physics, the foregoing inspired him to enter the field of Biophysics. In 1948–1950 he was at the Pasteur Institute and the Sorbonne in Paris, and in 1950–1952 at the laboratory of Jean Brachet, University of Brussels, where he initiated extensive studies on the properties of nucleic acid constituents and their analogs, including tautomerism, and relevance to mutagenesis, subsequently extended to polynucleotides, and photochemistry of proteins and nucleic acids. In 1952, he was invited to Warsaw, where he participated in organization of the Institute of Biochemistry & Biophysics, Polish Academy of Sciences, and then, at the invitation of the University, set up a Division of Biophysics in the Faculty of Physics. During this period, he was also a visiting professor at various centers such as Universite Laval (Quebec), National Research Council (Ottawa), and Universite Ghent (Belgium). Current research interests include: fluorescent probes for studies on biopolymer folding and function, enzyme kinetics and mechanisms; development of nucleoside analogs as antiviral agents; substrates/inhibitors of nucleoside and protein kinases; phosphate donors in kinase reactions; purine and pyrimidine nucleoside phosphorylases; and halogen bonding in biological systems. This year he is celebrating his 100 anniversary.

Doriano Fabbro, PhD in Biology, has 25 years of experience in drug discovery in Pharma (Ciba-Geigy, Novartis) as well as Biotech (Piqur Therapeutics) following 10 years in academia. Until 2005 he was Executive Director for the Oncology Drug Discovery effort at the Novartis Institute for Biomedical Research (NIBR) and a member of the NIBR Oncology Advisory Board overseeing a significant part of NIBR's global Oncology Drug Discovery portfolio from target discovery to clinical development. From 2005 to 2012 he was Executive Director of the NIBR Expertise Platform Kinases dedicated to global Kinase Drug Discovery Projects for several Oncology, Immunology, Inflammation, Respiratory Disease, Muscular Disease and Cardiovascular. Since 2012 he is Chief Scientific Officer of Piqur Therapeutics (Basel, Switzerland), a small company devoted to the discovery of PI3K/mTOR inhibitors as well as scientific advisor for several pharmaceutical companies in the area of kinase drug discovery. During his career he contributed to the development of Glivec® (Imatinib, BcrAbl inhibitor), Tasigna® (Nilotinib, BcrAbl inhibitor), Afinitor® (Everolimus, mTOR inhibitor) and many other compounds including Midostaurin (Kit and Flt-3 inhibitor), Alpelisib (PI3K inhibitor), Buparlisib (PI3K inhibitor), Vatalanib (VEGFR inhibitor), Luminespib (hsp90 inhibitor) and many more.

Jarek Poznański graduated in 1988 in Physics from Warsaw University, Physics Faculty, Biophysics Department. Since that time he is continuing his scientific career at the Institute of Biochemistry & Biophysics Polish Academy of Sciences, subsequently receiving there PhD, DSc and Prof. degrees in Life Sciences. Meanwhile, he has been in parallel working for over ten years at the Department of Calorimetry of the Institute of Physical Chemistry PAS, being involved in the development of data acquisition systems for various types of calorimeters. His actual scientific activities cover structure-related aspects of biomolecules in action. Current research interests include: data processing and analysis; molecular aspects of genetic diseases; structural preferences for Intrinsically Disordered Proteins; structural implications for biological processes deduced from medium-resolution models based on in silico Molecular Modeling supported by NMR, HDX-MS and IMS–MS data; thermodynamics of ligand binding deduced from ITC, DSC and DSF data. Since 2008, he has been closely collaborating with Prof. David Shugar in the studies on halogen bonding in protein–ligand systems.

David Shugar Institute of Biochemistry and Biophysics PAS, Pawińskiego 5a, 02-106 Warszawa, Poland Corresponding author E-mail address: [email protected] Doriano Fabbro PIQUR Therapeutics AG, Mattenstrasse 24A, CH-4058 Basel, Switzerland E-mail address: [email protected] Jarek Poznański Institute of Biochemistry and Biophysics PAS, Pawińskiego 5a, 02-106 Warszawa, Poland E-mail address: [email protected]

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Please cite this article as: D. Shugar, et al., Preface, Biochim. Biophys. Acta (2015),

8th International Conference on Inhibitors of Protein Kinases (IPK '2014).

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