Concepts and Case Studies in Chemical Biology

Introduction and Preface
Abbreviations

REAL-TIME AND CONTINUOUS SENSORS OF PROTEIN KINASE ACTIVITY UTILIZING CHELATION-ENHANCED FLUORESCENCE
Introduction
The Biological Problem
The Chemical Approach
Chemical Biological Research/Evaluation
Conclusions

FLiK AND FLiP: DIRECT BINDING ASSAYS FOR THE IDENTIFICATION OF STABILIZERS OF INACTIVE KINASE AND PHOSPHATASE CONFORMATIONS
Introduction - The Biological Problem
The Chemical Approach
Chemical Biological Research/Evaluation
Conclusions

STRATEGIES FOR DESIGNING SPECIFIC PROTEIN TYROSINE PHOSPHATASE INHIBITORS AND THEIR INTRACELLULAR ACTIVATION
Introduction - The Biological Problem
The Chemical Approach
Chemical Biological Research/Evaluation
Conclusions

DESIGN AND APPLICATION OF CHEMICAL PROBES FOR PROTEIN SERINE/THREONINE PHOSPHATASE ACTIVATION
Introduction
The Biological Problem
The Chemical Approach
Chemical Biological Research/Evaluation
Conclusion

AUTOPHAGY: ASSAYS AND SMALL-MOLECULE MODULATORS
Introduction
The Biological Problem
The Chemical Approach
Chemical Biological Evaluation
Conclusion

ELUCIDATION OF PROTEIN FUNCTION BY CHEMICAL MODIFICATION
Introduction
The Biological Problem
The Chemical Approach
Biological Research/Evaluation
Conclusion

INHIBITION OF ONCOGENIC K-Ras SIGNALING BY TARGETING K-Ras-PDEDelta
Introduction
The Biological Problem
The Chemical Approach
Chemical Biological Evaluation
Conclusions

DEVELOPMENT OF ACYL PROTEIN THIOESTERASE 1 (APT1) INHIBITOR PALMOSTATIN B THAT REVERT UNREGULATED H/N-Ras-SIGNALING
Introduction
The Biological Problem - The Role of APT1 in Ras Signaling
The Chemical Approach
Chemical Biological Research/Evaluation
Conclusions

FUNCTIONAL ANALYSIS OF HOST-PATHOGEN POSTTRANSLATIONAL MODIFICATION CROSSTALK OF RAB PROTEINS
Introduction
The Biological Problem
The Chemical Approach
Chemical Biological Research/Evaluation
Conclusions

CHEMICAL BIOLOGY APPROACH TO SUPPRESSION OF STATIN-INDUCED MUSCLE TOXICITY
Introduction
The Biological Problem
The Chemical Approach
Chemical Biological Research/Evaluation
Conclusion

A TARGET IDENTIFICATION SYSTEM BASED ON MORPHOBASE, CHEMPROTEOBASE, AND PHOTO-CROSS-LINKING BEADS
Introduction
The Biological Problem
The Chemical Approach
Chemical Biological Research/Evaluation
Conclusion

ACTIVITY-BASED PROTEASOME PROFILING IN MEDICINAL CHEMISTRY AND CHEMICAL BIOLOGY
Introduction
The Biological Problem
The Chemical Approach
Biological Research/Evaluation
Conclusions

RATIONAL DESIGN OF ACTIVITY-BASED RETAINING BETA-EXOGLUCOSIDASE PROBES
Introduction
The Biological Problem
The Chemical Approach
Biological Research/Evaluation
Conclusions

MODULATION OF ClpP PROTEASE ACTIVITY: FROM ANTIBIOTICS TO ANTIVIRULENCE
Introduction
The Biological Problem
The Chemical Approach
The Discovery of a Novel Antibiotic Mechanism
The Antivirulence Approach
Conclusions

AFFINITY-BASED ISOLATION OF MOLECULAR TARGETS OF CLINICALLY USED DRUGS
Introduction - The Biological/Medicinal Problem
The Chemical Approach
Chemical Biological Research
Conclusion

IDENTIFICATION OF THE TARGETS OF NATURAL-PRODUCT-INSPIRED MITOTIC INHIBITORS
Introduction
The Biological Problem
The Chemical Approach
Chemical Biological Evaluation
Conclusion

FINDING A NEEDLE IN A HAYSTAY. IDENTIFICATION OF TANKYRASE, A NOVEL THERAPEUTIC TARGET OF THE WNT PATHWAY USING CHEMICAL GENETICS
Introduction
The Biological Problem
The Chemical Approach
Chemical Biological Research/Evaluation
Conclusion

THE IDENTIFICATION OF THE MOLECULAR RECEPTOR OF THE PLANT HORMONE ABSCISIC ACID
Introduction
The Biological Problem
The Chemical Genetics Approach
The Chemical Biology Approach
Conclusion

CHEMICAL BIOLOGY IN PLANTS: FINDING NEW CONNECTIONS BETWEEN PATHWAYS USING THE SMALL MOLECULE SORTIN 1
Introduction
The Biological Problem
The Chemical Approach
Biological Research/Evaluation
Conclusion

SELECTIVE TARGETING OF PROTEIN INTERACTIONS MEDIATED BY BET BROMODOMAINS
Introduction
The Biological Problem
The Chemical Approach
Chemical Biological Investigations
Conclusion

THE IMPACT OF DISTANT POLYPHARMACOLOGY IN THE CHEMICAL BIOLOGY OF PARPS
Introduction
The Biological Problem
The Chemical Approach
Chemical Biological Research/Evaluation
Conclusions

SPLICING INHIBITORS: FROM SMALL MOLECULE TO RNA METABOLISM
Introduction
The Biological Problem
The Chemical Approach
Chemical Biological Research/Evaluation
Conclusion

PHOTOCHEMICAL CONTROL OF GENE FUNCTION IN ZEBRAFISH EMRYOS WITH LIGHT-ACTIVATED MORPHOLINOS
Introduction
The Biological Problem
The Chemical Approach
Chemical Biological Research/Evaluation
Conclusion

LIFE CELL IMAGING OF mRNA USING PNA FIT PROBESIntroduction
The Biological Problem
The Chemical Approach
Chemical Biological Research/Validation
Conclusion

TARGETING THE TRANSCRIPTIONAL HUB BETA-CATENIN USING STAPLED PEPTIDES
Introduction
The Biological Problem
The Chemical Approach: Hydrocarbon Peptide Stapling
The Biological Approach: Phage-Display-Based Optimization
Biochemical and Biological Evaluation
Conclusions

DIVERSITY-ORIENTED SYNTHESIS: DEVELOPING NEW CHEMICAL TOOLS TO PROBE AND MODULATE BIOLOGICAL SYSTEMS
Introduction
The Biological Problem
The Chemical Approach
Chemical Biology Research
Conclusion

SCAFFOLD DIVERSITY SYNTHESIS WITH BRANCHING CASCADES STRATEGY
Introduction
The Biological/Pharmacological Problem: Discovering Small Bioactive Molecules
The Chemical Approach: Scaffold Diversity
Chemical/Biological Evaluation - Branching Cascades Strategy in Scaffold Diversity Synthesis
Conclusions

Index

Herbert Waldmann obtained his PhD in organic chemistry from the University of Mainz, Germany, in 1985 working with Professor H. Kunz, after which he completed a postdoctoral appointment with Professor G. Whitesides at Harvard University (USA). He was appointed as Professor of Organic Chemistry at the University of Bonn (1991), full Professor of Organic Chemistry at the University of Karlsruhe (1993), and Director at the Max-Planck-Institute of Molecular Physiology Dortmund and Professor of Organic Chemistry at the University of Dortmund, Germany, in 1999. He has received numerous awards, e.g. the Otto-Bayer-Award (2001), the Max Bergmann Medal (2003), and recently the Emil-Fischer-Prize (2012). His research interests lie in bioactive compound development, target identification, and the chemical biology of Ras proteins.

Petra Janning studied chemistry at the University of Münster, Germany, and did her PhD thesis at the Institute for Analytical Sciences in Dortmund, Germany in 1995. After different positions where she worked in the area of analytical chemistry and on the borderline between chemistry and biology she joined the Max-Planck-Institute of Molecular Physiology, Dortmund, in the department of Professor H. Waldmann, where she is currently working. She is responsible for the Bioorganic Practical Course and the analytics in the department. She focused her work on mass spectrometry based methods in proteome research in particular in target protein identification of small molecules.