Cellular & Molecular Biology Letters

International Scientific Journal
Established 1996

Volume 10 (2005) Supplement 2

IPK'2005

4th International Conference on Inhibitors of Protein Kinases

and

Workshop on Modelling of Specific Molecular Recognition Processes

June 25 - 29, 2005, Warsaw, Poland

DESIGN * STRUCTURAL BIOLOGY * PHOSPHORYLATION/ DEPHOSPHORYLATION MECHANISMS * SIGNALING PATHWAYS * BIOCHEMISTRY * BIOTECHNOLOGY * CLINICAL ASPECTS * CHEMOTHERAPY

Volume 10 (2005) pp 9
Title	PREFACE
Authors	David Shugar
	This special issue of Cellular & Molecular Biology Letters presents the Abstracts of Invited Lectures, and of submitted accepted posters (several of which have been selected for short oral presentation) to the 4th International Conference on INHIBITORS OF PROTEIN KINASES (IPK’2005), to take place in Warsaw, Poland, June 25-29, 2005. Also included are Abstracts of several invited lectures, and submitted posters, at an associated Workshop on “Modelling of Specific Molecular Recognition Processes”, and relevance to protein kinases. Protein phosphorylation is widely recognized as the most important pathway for regulation of protein functions in living cells, by switching cellular activities from one state to another and, in this way, regulating gene expression, cell proliferation and differentiation. It is the major mechanism whereby cells respond to extracellular signals, such as hormones and growth factors, thus controlling all events at various stages of the cell cycle, as well as the response of the cell to environmental and nutritional stress. Reversible protein phosphorylation is catalyzed by the interplay between protein kinases and protein phosphatases. Given the key role of protein kinases in signal transduction, it was to be anticipated that this would stimulate searches for inhibitors. But, in striking contrast to other enzyme systems, more than 500 protein kinases have now been identified in the human genome alone, all of them catalyzing a similar reaction. It would therefore appear to be a formidable task to develop potent, selective, and cell-permeable, inhibitors for a given kinase. However, a variety of sophisticated approaches, both experimental and theoretical, directed towards this goal have resulted in remarkable progress, as will be seen from the Abstracts in a session on this subject. Notwithstanding the fact that most of them are ATPcompetitive, it is clear that subtle differences in the unique conformations of the catalytic pockets (conformational flexibility, induced fit) play a key role in determining selectivity. Many relatively selective inhibitors are now routinely employed in experiments designed to delineate signal transduction pathways. In this context, it is worth noting, as pointed out recently by Doriano Fabbro of Novartis [Assays & Drug Develop. Technol. 2 (2004) 2-6], that “availability of a good lead (compound) is the key to successful optimization and is much more important than the availability of a structure of the target”. This is in line with our own experience in the initial development of tetrabromo- benzotriazole and benzimidazole selective cell-permeable inhibitors of protein kinase CK2 from various sources. But, once a good lead compound has been identified, by whatever means, subsequent structure-based design for further optimization has decisively demonstrated its merits. Furthermore, it has long been known that dysfunctions in activities of protein kinases (and phosphatases) may lead to severe pathological states. It is consequently not surprising that the Biotechnology sector, frequently in collaboration with Academia, is presently devoting major efforts (30 – 40% of their research budgets) to “targeting” protein kinases for drug development, with considerable achievements to date, Gleevec being a prime, but by no means the only, example. It is, consequently, most appropriate that, as at previous IPK meetings, participants at the present Conference include representatives of some major Biotechnology firms actively engaged in this field. A novel feature of the 3rd International Conference (IPK’2003) was a special session on the newly emerging field of protein kinases of pathogenic agents such as viruses, parasites and fungi. Bearing in mind current world-wide efforts to cope with diseases such as malaria (which alone is responsible for more than 1 million deaths annually), caused by protozoan parasites, the present Conference includes a special session on the protein kinases of parasitic protozoa, as well as of their host cells, and accompanying efforts to develop inhibitors of these enzymes as therapeutic agents. Another field that is slowly coming to the forefront is that of histidine kinases of the two-component type, hitherto well characterized in bacteria, plants and fungi. There is now compelling evidence for such enzymes in mammalian cells, and two speakers at this meeting will present up-to-date reviews on what is known about histidine kinases and histidine phosphatases in mammalian systems. We wish to express our appreciation to members of the International Advisory Board for assistance in organizing the program and, in particular, to Christian Doerig and Laurent Meijer for their help in preparing the sessions on parasite kinases and selective kinase inhibitors, respectively. We are indebted to most of the contributors to this Conference, who have complied with our request for Abstracts that are informative, including key references; and to Barbara Kleyny of the IPK Secretariat for her unstinting efforts in checking their conformity with the requirements of the journal.

Volume 10 (2005) pp 11-91
Invited Lectures
Abstracts List	CONTROLLING SUBSTRATE SPECIFICITY IN PROTEIN KINASES THROUGH CHEMICAL CLAMPING Joseph A. Adams - p13 MAMMALIAN HISTIDINE KINASES Paul V. Attwood and Paul G. Besant - p16 ATP-NONCOMPETITIVE INHIBITORS OF THE C-JUN N-TERMINAL KINASE (JNK) SUBFAMILY - WHAT CAN THEY OFFER? Marie A. Bogoyevitch and Renae K. Barr - p19 SCREENING ERK2 PROTEIN AND PEPTIDE ASSOCIATIONS BY FLUORESCENCE ANISOTROPY: INSIGHTS INTO ERK2 FUNCTION AND REGULATION BY PROTEIN-PROTEIN INTERACTIONS Kari Callaway, Mark Rainey and Kevin N. Dalby - p22 ANALYSIS AND CHARACTERISATION OF PROTEIN KINASE INHIBITOR SELECTIVITY AND FUNCTION Henrik Daub - p25 REGULATORY FUNCTIONS OF SERYL-PHOPHORYLATED HPr IN PATHOGENIC BACTERIA Josef Deutscher, Rana Herro and Sandrine Poncet - p28 PROTEIN KINASES OF PARASITIC PROTOZOA AND THEIR HOST CELLS: TARGETS FOR CHEMOTHERAPEUTIC INTERVENTION? Christian Doerig - p30 THE P. falciparum CDK FAMILY: STRUCTURAL STUDIES AND IMPLICATIONS FOR INHIBITOR DESIGN Anais Merckx, Alex Zawaira, Simon Holton, Christian Doerig, Martin Noble and Jane Endicott - p33 DOMAIN TRUNCATION, POINT MUTATION, AND SURROGATION FOR STRUCTURE BASED KINASE INHIBITOR DESIGN Christine B. Breitenlechner, Robert Huber, Dirk Bossemeyer, Michael Gassel, Birgit Masjost and Richard A. Engh - p35 TARGETING MALARIA WITH SPECIFIC CDK INHIBITORS Jeanne A. Geyer, April K. Kathcart, Apurba K. Bhattacharjee, Yueqin Chen, Edison A. Cortes, Sean T. Prigge and Norman C. Waters - p38 MANIPULATION OF ALTERNATIVE SPLICING BY SPECIFIC INHIBITORS OF SR PROTEIN KINASES Masatoshi Hagiwara - p40 BAKER'S YEAST AS A TOOL FOR THE DEVELOPMENT OF ANTIFUNGAL KINASE INHIBITORS - TARGETING PROTEIN KINASE C AND THE CELL INTEGRITY PATHWAY Jürgen J. Heinisch - p42 IMMUNOSUPPRESSANTS AS NOVEL ANTI-INFLAMMATORY DRUGS AFFECTING MAPK SIGNALLING PATHWAYS Bożena Kamińska - p45 DIACYLGLYCEROL SIGNALING: TARGETING PROTEIN KINASE C ISOZYMES AND "NON-KINASE" DIACYLGLYCEROL EFFECTORS Marcelo G. Kazanietz - p47 SCANNING THE PROTEOME FOR TARGETS OF KINASE INHIBITORS USING BI-FUNCTIONAL RECEPTOR LIGANDS Nikolai Kley - p50 REVERSIBLE PHOSPHORYLATION OF HISTIDINE RESIDUES IN VERTEBRATE PROTEINS Susanne Klumpp, Anette Maeurer, Thomas Wieland and Josef Krieglstein - p52 PREDICTION OF SUBSTRATE SPECIFICITIES OF PROTEIN KINASES Boštjan Kobe and Ross I. Brinkworth - p54 THE RIO KINASES: STRUCTURAL STUDIES OF A FAMILY OF ATYPICAL PROTEIN KINASES REQUIRED FOR RIBOSOME BIOGENESIS AND CELL CYCLE PROGRESSION Nicole LaRonde-LeBlanc and Alexander Wlodawer - p57 SIGNALING PROTEIN INHIBITORS via THE COMBINATORIAL MODIFICATION OF PEPTIDE SCAFFOLDS David S. Lawrence - p60 ADVANCES IN THE STRUCTURAL BIOLOGY, DESIGN AND CLINICAL DEVELOPMENT OF BCR-ABL KINASE INHIBITORS FOR THE TREATMENT OF CHRONIC MYELOGENOUS LEUKEMIA Paul W. Manley, Sandra Cowan-Jacob and Jürgen Mestan - p62 THE SELECTIVITY OF PHARMACOLOGICAL INHIBITORS OF CYCLIN-DEPENDENT KINASES (CDKS) AND GLYCOGEN SYNTHASE KINASE -3 (GSK-3) Laurent Meijer - p66 PROTEIN KINASES OF TRYPANOSOMATIDS AS DRUG TARGETS Jeremy C. Mottram, Christina Naula, Tansy Hammarton and Marilyn Parsons - p69 DESIGNING SPECIFIC INHIBITORS OF THE BACTERIAL HPr KINASE / PHOSPHORYLASE Sylvie Nessler - p71 EXPLOITING STRUCTURAL PRINCIPLES TO GENERATE PROTEIN KINASE INHIBITORS Martin Noble, Paul Barrett, Jane Endicott, Louise Johnson, Jim Mcdonnell, David Pratt and Giles Robertson - p74 THE ROLE OF SMG-1, A MEMBER OF THE PIKK (PHOSPHOINOSITIDE 3-KINASE RELATED KINASES ) FAMILY, IN mRNA SURVEILLANCE; MOLECULAR MECHANISM AND THERAPEUTIC IMPLICATIONS Shigeo Ohno - p76 FEATURES AND POTENTIALS OF ATP-SITE DIRECTED CK2 INHIBITORS Lorenzo A. Pinna - p78 PROTEIN KINASE STRUCTURE AND FUNCTION ANALYSIS WITH CHEMICAL TOOLS Kui Shen, Aliya C. Hines, Dirk Schwarzer, Kerri P. Paumi and Philip A. Cole - p81 DEVELOPMENT OF SPECIFIC RHO-KINASE INHIBITOR AND ITS CLINICAL APPLICATION Masahiro Tamura and Hiroyoshi Hidaka - p83 DYNAMICS OF SIGNALING BY PKA Susan S. Taylor, Dominico Vigil, Donald Blumenthal, Jill Trewhella, Choel Kim, Ganesh Anand, David Johnson and Jie Yang - p85 INVOLVEMENT OF THE SMALL PROTEIN TYROSINE PHOSPHATASES TC-PTP AND PTP1B SIGNAL TRANSDUCTION IN DISEASES; FROM DIABETES, OBESITY TO CELL CYCLE AND CANCER Michel L. Tremblay - p88 DISSECTING THE FUNCTIONS OF PROTEIN TYROSINE PHOSPHATASES USING CHEMICAL APPROACHES Zhong-Yin Zhang - p89

Posters
Abstracts List	MECHANISM OF INHIBITION OF THE PROTEIN KINASE C BY NONSTRUCTURE PROTEIN 3 OF HEPATITIS C VIRUS Philip Hartjen, Michael Reinholz, Andrea Baier and Peter Borowski - p95 DEPENDENCE OF AMINOGLYCOSIDE 3’-PHOSPHOTRANSFERASE VIII ACTIVITY AND ANTIBIOTIC RESISTANCE ON Ca2+-DEPENDENT PROTEIN SERINE/THREONINE KINASES IN ACTINOMYCETES Valery N. Danilenko, Sergei M. Elizarov and Maria G. Alekseeva - p97 ORALLY-ACTIVE PYRIDOPYRIMDINE INHIBITORS OF TRANSFORMING GROWTH FACTOR BETA RI (ALK5) KINASE. STRUCTURE AND ACTIVITY, in-vitro AND in-vivo CHARACTERIZATION Sarvajit Chakravarty and Sundeep Dugar - p99 ISOFLAVONOIDS AND THEIR 3’ AND 4’-O-SUBSTITUED DERIVATIVES AS INHIBITORS OF SH2 DOMAIN OF p56lck PROTEIN TYROSINE KINASE Agnieszka Godlewska, Rafał Augustyniak and Paweł Bodera - p100 EVALUATION OF 3-CARBOXY-4-(1H)-QUINOLONES AS INHIBITORS OF HUMAN PROTEIN CASEIN KINASE 2 Andriy G. Golub, Volodymyr G. Bdzhola, Olexander Ya. Yakovenko, Vladislav M. Sapelkin and Sergiy M. Yarmoluk - p102 EFFECT OF TRICHOSTATIN A ON TRANSCRIPTION OF SELECTED SIGNAL MOLECULE GENES IN JURKAT T CELLS Radosław Januchowski and Paweł P. Jagodziński - p103 mTOR AND p70S6K PHOSPHORYLATION BY INSULIN ą RAPAMYCIN IN HepG2 CELLS WITH AND WITHOUT OVEREXPRESSION OF CONSTITUTIVELY ACTIVE Akt/PKB Shailly Varma, Dhanajay Gupta and Ramji L. Khandelwal - p105 SEARCHING FOR INHIBITORS OF CDPK AS POTENTIAL DRUGS AGAINST PARASITES? Maria Klimecka, Jadwiga Szczegielniak, Luiza Koper, Marcin Kośliński and Grażyna Muszyńska - p107 INSULIN-LIKE GROWTH FACTOR-1 INITIATES A NEGATIVE FEED BACK MECHANISM BY JNK ACTIVATED SHP1 TO REGULATE PROLIFERATION OF BREAST CANCER CELLS Shahreen Amin, Ashok Kumar, Joan Lee and Maya Kozlowski - p108 MOLECULAR DYNAMICS STUDY OF PROTEIN-LIGAND INTERACTIONS Zdeněk Kříž, Michal Otyepka, Iveta Bártová and Jaroslav Koča - p111 CYCLIN-DEPENDENT KINASE INHIBITOR OLOMOUCINE II INTERACTS WITH CDK2 AND CDK9 Vladimír Kryštof, Martin Orság, Martina Paprskářová, Petr Müller, Bořivoj Vojtěšek and Miroslav Strnad - p113 MOLECULAR DYNAMICS SIMULATIONS OF PHOSPHOLAMBAN: EFFECTS OF MEMBRANE, PHOSPHORYLATION AND AGGREGATION Yao Houndonougbo, Gouri S. Jas and Krzysztof Kuczera - p114 DYNAMICS OF HUMAN CDK2 AND CDK5 STUDIED BY COMPUTER SIMULATIONS Michal Otyepka, Iveta Bártová, Zdeněk Kříž and Jaroslav Koča - p116 THE INTERACTION BETWEEN PROTEIN KINASE C EPSILON AND FOCAL ADHESION KINASE Ewa Totoń, Johann Hofmann and Maria Rybczyńska - p118 THE PHYSICAL NATURE OF CAMP-DEPENDENT PROTEIN KINASE CATALYTIC ACTIVITY: AB INITIO DIFFERENTIAL TRANSITION STATE STABILIZATION ANALYSIS OF THE KEY ACTIVE SITE RESIDUES Paweł Szarek, Edyta Dyguda, W. Andrzej Sokalski, Yuhui Cheng, Yingkai Zhang and J. Andrew McCammon - p119 ASF1 - YEAST INDUCTOR OF APOPTOSIS INHIBITS CK2 ACTIVITY in vitro Monika Jach, Konrad Kubiński, Rafał Zieliński, Ewa Sajnaga and Ryszard Szyszka - p121 IP6 MODULATES INTERLEUKIN-8 SECRETION IN COLON EPITHELIAL CELLS BY INFLUENCING VARIOUS SIGNALING PATHWAYS Ludmiła Węglarz, Joanna Wawszczyk, Arkadiusz Orchel and Zofia Dzierżewicz - p124 IMPLEMENTATION OF ORBITAL GRAPH MODEL FOR PARTIAL ATOM CHARGES DEFINITION IN VIRTUAL SCREENING TECHNIQUES Olexander Ya. Yakovenko, Andriy G. Golub, Volodymyr G. Bdzhola and Sergiy M. Yarmoluk - p126

Abstracts of posters selected for oral presentation
Abstracts List	NAVIGATING CROSS-KINASE SELECTIVITY SPACE Alex M. Aronov, Brian Mcclain, Paul R. Caron and Mark A. Murcko - p129 MALARIA PARASITE TRANSMISSION TO THE MOSQUITO IS REGULATED BY UNUSUAL PROTEIN KINASES WITH STAGE-SPECIFIC ESSENTIAL FUNCTIONS Oliver Billker, Christian Doerig, Rita Tewari, Inga Siden-Kiamos, Robert Moon and Dominique Dorin 131 ALK 5 (TGF BETA RI) INHIBITORS: In-vitro AND In-vivo CHARACTERIZATION OF NOVEL ORALLY ACTIVE PTERIDINES Sarvajit Chakravarty and Sundeep Dugar - p133 A NOVEL NON-CATALYTIC INHIBITORY MECHANISM EMPLOYED BY THE CSK-HOMOLOGOUS KINASE (CHK) TO INACTIVATE SRC-FAMILY PROTEIN KINASES Heung-Chin Cheng, Yuh-Ping Chong and Terrence Mulhern - p135 CLASSIFICATION AND CHARACTERIZATION OF NATURAL PROTEIN INHIBITORS OF PROTEIN KINASES Agata Meglicz, Jacek Leluk and Bogdan Lesyng - p137 IMPLICATIONS OF KINASE SIMILARITY IN DRUG DISCOVERY Michal Vieth and Jeffrey Sutherland - p139 TETRABROMOBENZOTRIAZOLE (TBBt) AND TETRABROMOBENZIMIDA-ZOLE (TBBz): SELECTIVE INHIBITORS OF PROTEIN KINASE CK2, AND THEIR INFLUENCE ON ACTIVITIES OF DIFFERENT FORMS OF HUMAN CK2, AND ON THE CELLS Piotr Zień, David W. Litchfield, James Duncan, Janusz Skierski, Maria Bretner and David Shugar - p141

Workshop on modelling of specific molecular recognition processes
Abstracts List	ALTERNATIVE BINDING MODES OF PROLINE-RICH PEPTIDES BINDING TO THE GYF DOMAIN Wei Gu, Michael Kofler, Iris Antes, Christian Freund and Volkhard Helms - p145 TARGET FLEXIBILITY IN MOLECULAR RECOGNITION J. Andrew McCammon - p146 MULTIPLE MOLECULAR RECOGNITION MECHANISMS. CYTOCHROME P450 – A CASE STUDY Rebecca C. Wade, Domantas Motiejunas, Karin Schleinkofer, Sudarko, Peter J. Winn and Amit Banerjee - p147 RAPID PROTEIN-LIGAND DOCKING USING SOFT MODES FROM MD SIMULATIONS TO ACCOUNT FOR PROTEIN DEFORMABILITY: APPLICATION TO PROTEIN KINASE-LIGAND INTERACTIONS Martin Zacharias - p149

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