ChemBioChem

Cover image for ChemBioChem

Special Issue: Kinases in Drug Discovery

March 4, 2005

Volume 6, Issue 3

Pages 453–574

    1. Cover Picture: The Target Discovery Process (ChemBioChem 3/2005) (page 453)

      Ursula Egner, Jörn Krätzschmar, Bertolt Kreft, Hans-Dieter Pohlenz and Martin Schneider

      Article first published online: 1 MAR 2005 | DOI: 10.1002/cbic.200590008

      The cover picture shows the target discovery process as implemented at Schering AG for work on kinases. Before a target enters the lead discovery phase, the target candidate has to pass several hurdles to maximise the likelihood of achieving target-selective inhibition by small-molecule inhibitors. This target-discovery process comprises three phases: target identification, drugability assessment and functional target validation. Further details can be found in the article of U. Egner et al. on p. 468 ff.

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      Editorial: Drug Discovery Process for Kinease Inhibitors (pages 455–459)

      Hilmar Weinmann and Rainer Metternich

      Article first published online: 1 MAR 2005 | DOI: 10.1002/cbic.200500034

    3. Graphical Abstract: ChemBioChem 3/2005 (pages 460–464)

      Article first published online: 1 MAR 2005 | DOI: 10.1002/cbic.200590009

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      The Selectivity for Cysteine over Serine in Coenzyme A Biosynthesis (page 463)

      Erick Strauss and Tadhg P. Begley

      Article first published online: 1 MAR 2005 | DOI: 10.1002/cbic.200590010

    5. The Target Discovery Process (pages 468–479)

      Ursula Egner, Jörn Krätzschmar, Bertolt Kreft, Hans-Dieter Pohlenz and Martin Schneider

      Article first published online: 1 MAR 2005 | DOI: 10.1002/cbic.200400158

      Thumbnail image of graphical abstract

      Minimising attrition rates in drug development. The target discovery process implemented at Schering AG while working on kinases consists of target selection (see gene expression profile), assessment and validation. This rational approach, as a prerequisite for lead discovery, ensures that new therapeutic targets fulfill a set of indication-specific, descriptive and functional criteria, and this should maximise the likelihood of achieving target-selective inhibition with minimal side effects and a therapeutic effect based on a sound biological hypothesis.

    6. High-Throughput Screening for Kinase Inhibitors (pages 481–490)

      Oliver von Ahsen and Ulf Bömer

      Article first published online: 1 MAR 2005 | DOI: 10.1002/cbic.200400211

      Looking for a lead. After G protein-coupled receptors (GPCRs), protein kinases are the second most important class of targets for drug discovery. The 518 protein kinases in the human genome are now regarded as attractive drug targets. Screening for protein kinase inhibitors is therefore expected to become even more important in the future. In this review the early steps of drug discovery programs that produce new lead compounds are described and the reader is guided through efficient state-of-the-art assay development and high-throughput screening of large chemical libraries for protein kinase inhibitors.

    7. Relevance of Atypical Protein Kinase C Isotypes to the Drug Discovery Process (pages 491–499)

      Marcel Jenny, Oliver A. Wrulich, Wolfgang Schwaiger and Florian Ueberall

      Article first published online: 11 FEB 2005 | DOI: 10.1002/cbic.200400186

      Cell proliferation and cell death in tumours are molecular mechanisms that underlie the interplay of proliferation and apoptosis. Atypical protein kinase C isotypes possess a so-called OPCA motif with novel regulatory domain characteristics potentially exploitable for antitumour pharmaceutical intervention.

    8. Target-Family-Oriented Focused Libraries for Kinases—Conceptual Design Aspects and Commercial Availability (pages 500–505)

      Olaf Prien

      Article first published online: 1 MAR 2005 | DOI: 10.1002/cbic.200400117

      Tailor-made libraries may increase the likelihood of identifying potential lead candidates in early drug-discovery phases. That at least 12 commercial vendors offer their services in providing compound collections of tentative kinase inhibitors reflects the growing interest in kinases within the pharmaceutical industry. Some conceptual design approaches for focused library design for the kinase family are reviewed, and the design concepts of these commercialized libraries is discussed.

    9. The Discovery of Novel Protein Kinase Inhibitors by Using Fragment-Based High-Throughput X-ray Crystallography (pages 506–512)

      Adrian Gill, Anne Cleasby and Harren Jhoti

      Article first published online: 4 FEB 2005 | DOI: 10.1002/cbic.200400188

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      Divide and screen. Many human diseases involve aberrant protein kinase activity, and the hunt for novel and druglike protein kinase inhibitors continues apace. The use of high-throughput X-ray crystallographic fragment-based screening to identify low-molecular-weight leads (see figure) for structure-based optimisation into protein kinase inhibitors is a powerful tool for drug discovery.

    10. Peptide Arrays for Kinase Profiling (pages 513–521)

      Mike Schutkowski, Ulrich Reineke and Ulf Reimer

      Article first published online: 1 MAR 2005 | DOI: 10.1002/cbic.200400314

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      Hundreds and thousands of simultaneous kinase assays are possible by using peptide arrays. In this minireview, we summarize production principles, library types, and assay strategies used for kinase profiling on peptide arrays. The second part gives a comprehensive review of the various peptide microarray applications in kinase research.

    11. Small-Molecule Kinase-Inhibitor Target Assessment (pages 523–526)

      Charles Kung and Kevan M. Shokat

      Article first published online: 7 FEB 2005 | DOI: 10.1002/cbic.200400393

      There is a growing realization that protein kinase inhibitors might need to inhibit multiple kinases in order to achieve their therapeutic effects. Thus, the cellular effects of a kinase inhibitor might not be fully understood by considering individual kinase-inhibitor interactions in isolation. We describe a chemical-genetic strategy that should help identify cellular targets of kinase inhibitors and to link these targets to the cellular phenotypes that arise when they are inhibited individually or in combination.

    12. Inhibition of Angiogenesis-Relevant Receptor Tyrosine Kinases by Sulindac Analogues (pages 527–531)

      Eleni Gourzoulidou, Mercedes Carpintero, Patrick Baumhof, Athanassios Giannis and Herbert Waldmann

      Article first published online: 4 FEB 2005 | DOI: 10.1002/cbic.200400192

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      It's in the blood. Analogues (see formula) of the non-steroidal inflammatory drug Sulindac are potent and selective inhibitors of the angiogenesis-related receptor tyrosine kinases VEGFR-2 and -3, IGF1R, FGF1R and Tie-2; this suggests a possible link between the antiangiogenic properties of Sulindac metabolites and kinase inhibition.

    13. From the Insoluble Dye Indirubin towards Highly Active, Soluble CDK2-Inhibitors (pages 531–540)

      Rolf Jautelat, Thomas Brumby, Martina Schäfer, Hans Briem, Gerhard Eisenbrand, Stefan Schwahn, Martin Krüger, Ulrich Lücking, Olaf Prien and Gerhard Siemeister

      Article first published online: 1 MAR 2005 | DOI: 10.1002/cbic.200400108

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      In search of novel antitumor therapies. The natural product indirubin (1) is one of the class of indigo dyes, insoluble in aqueous systems, employed by mankind since the Bronze Age for textile coloring. In 1999 indirubin was reported to be a modest inhibitor of the enzyme CDK2, a key target in the ongoing search for novel antitumor therapies. With the guidance of X-ray structures, indirubin was transformed to yield novel, soluble, almost colorless, highly potent CDK2 inhibitors that strongly inhibit the growth of the MCF7 tumor cell line in vitro.

    14. Structure-Aided Optimization of Kinase Inhibitors Derived from Alsterpaullone (pages 541–549)

      Conrad Kunick, Zhihong Zeng, Rick Gussio, Daniel Zaharevitz, Maryse Leost, Frank Totzke, Christoph Schächtele, Michael H. G. Kubbutat, Laurent Meijer and Thomas Lemcke

      Article first published online: 4 FEB 2005 | DOI: 10.1002/cbic.200400099

      Thumbnail image of graphical abstract

      Additional hydrophobic contacts in the gateway area of the ATP-binding pocket are made by the side chains that were added to the alsterpaullone molecule in the course of a structure-aided optimization strategy for kinase inhibitors. In the case of the 2-cyanoethyl alsterpaullone (depicted in orange), the side chain addition led to a more than hundredfold increase in inhibitory activity on the cyclin-dependent kinase1/ cyclin B complex.

    15. PTK 787/ZK 222584, a Tyrosine Kinase Inhibitor of all Known VEGF Receptors, Represses Tumor Growth with High Efficacy (pages 550–557)

      Holger Hess-Stumpp, Martin Haberey and Karl-Heinz Thierauch

      Article first published online: 1 MAR 2005 | DOI: 10.1002/cbic.200400305

      Thumbnail image of graphical abstract

      Best of both worlds. The combination of cytostatics with angiogenesis kinase inhibitors requires selectivity. Reversibility of action will permit mandatory rapid surgery. PTK/ZK (1), a multi-VEGFR kinase inhibitor of excellent selectivity and potency fulfills these criteria, as shown here.

    16. Classifying “Kinase Inhibitor-Likeness” by Using Machine-Learning Methods (pages 558–566)

      Hans Briem and Judith Günther

      Article first published online: 7 FEB 2005 | DOI: 10.1002/cbic.200400109

      Thumbnail image of graphical abstract

      Teaching the machine. By using a set of in-house compounds, four different machine-learning techniques (SVM, ANN, GA/kNN, and RP) were applied to distinguish active kinase inhibitors from “inactives”. The machine-learning methods showed clear differences in performance, exemplified here by the F1 measure. Moreover, applying a majority-voting scheme based on different single models outperformed simple averaging over the models.

    17. Kinase Data Mining: Dealing with the Information (Over-)Flow (pages 567–570)

      Knut Eis, Stuart J. Ince, Carsten Jahn, Rolf Jautelat, Vladimir Katchourovsky, Georg Kettschau and Rolf Woloszczak

      Article first published online: 11 FEB 2005 | DOI: 10.1002/cbic.200400154

    18. Preview: ChemBioChem 3/2005 (page 574)

      Article first published online: 1 MAR 2005 | DOI: 10.1002/cbic.200590011

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