Target Identification and Validation in Drug Discovery Methods and Protocols by Moll, Jurgen, Colombo, Riccardo (Eds.)

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Target Identification and Validation in Drug Discovery

Methods and Protocols

SeriesMethods in Molecular Biology, Vol. 986

Moll, Jurgen, Colombo, Riccardo (Eds.)

2013, XV, 371 p. 62 illus., 19 illus. in color.

 

  • Includes cutting-edge methods and protocols
  • Provides step-by-step detail essential for reproducible results
  • Contains key notes and implementation advice from the experts

The major reason for the elevated costs of drug development in the pharmaceutical industry is the high attrition rate. In Target Identification and Validation in Drug Discovery: Methods and Protocols, expert researchers in the field detail many of the methods which are now commonly used to identify and validate new target. These include methods and approaches covering biochemical, cell based, in vivo models and translational methods. Chapters also include selected case reports that demonstrate the integration of these technologies to real life experiences and to demonstrate the multiple use of more than one technology to increase knowledge on a specific target. These Written in the highly successful Methods in Molecular Biology™ series format, the chapters include the kind of detailed description and implementation advice that is crucial for getting optimal results in the laboratory.

 

Thorough and intuitive, Target Identification and Validation in Drug Discovery: Methods and Protocols contains a comprehensive list of essential methods and clear protocols to follow.

Content Level » Professional/practitioner

Keywords » Omics Oncology biochemical cell based cell culture technologies drug development in vivo models in-silico translational methods

 

Contents
Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii
PART I BACKGROUND
 1 The Path to Oncology Drug Target Validation: An Industry Perspective . . . . . 3
Marta Cortés-Cros, Tobias Schmelzle, Volker M. Stucke, 
and Francesco Hofmann
PART II DNA AS A TOOL TO MODULATE DRUG TARGETS
 2 Identification of Aptamers as Specific Binders and Modulators 
of Cell-Surface Receptor Activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Henning Ulrich and Carsten Wrenger 
 3 The Design and Structure–Functional Properties 
of DNA-Based Immunomodulatory Sequences . . . . . . . . . . . . . . . . . . . . . . . . 41
Nikolai V. Kuznetsov
PART III RNA INTERFERENCE: FROM DESIGN TO DATA ANALYSIS
 
4 siRNA Design Principles and Off-Target Effects . . . . . . . . . . . . . . . . . . . . . . . 59
Sebastian Petri and Gunter Meister 
 
5 Western Blot Evaluation of siRNA Delivery by pH-Responsive Peptides . . . . . 73
Wanling Liang, A. James Mason, and Jenny K.W. Lam 
 
6 High-Throughput RNAi Screening for the Identification 
of Novel Targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Meredith C. Henderson and David O. Azorsa 
 7 Integration of RNAi and Small Molecule Screens to Identify Targets 
for Drug Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Konstantinos Drosopoulos and Spiros Linardopoulos 
 
8 CellProfiler and KNIME: Open Source Tools for High 
Content Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Martin Stöter, Antje Niederlein, Rico Barsacchi, Felix Meyenhofer, 
Holger Brandl, and Marc Bickle 
 9 PARP Inhibition as a Prototype for Synthetic Lethal Screens . . . . . . . . . . . . . . 123
Xuesong Liu x Contents
PART IV PROTEIN-FOCUSED TECHNOLOGIES
10 Structure-Based Target Druggability Assessment. . . . . . . . . . . . . . . . . . . . . . . 141
Jean-Yves Trosset and Nicolas Vodovar 
11 Validating Pharmacological Disruption of Protein–Protein Interactions 
by Acceptor Photobleaching FRET Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . 165
Janos Roszik, Gábor Tóth, János Szöllősi, and György Vereb 
12 Systematic Analysis of Complex Signal Transduction Pathways 
Using Protein Fragment Complementation Assays . . . . . . . . . . . . . . . . . . . . . 179
Thomas I. Koblizek, Ann Siehoff, and Anthony Pitt 
13 Reverse Phase Protein Microarrays and Their Utility in Drug 
Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
Maria Isabella Sereni, Mariaelena Pierobon, Roberto Angioli, 
Emanuel F. Petricoin III, and Mitchell J. Frederick 
PART V INNOVATIVE CELL CULTURE TECHNIQUES TO MIMIC TISSUE 
MICROENVIRONMENTS
14 A Cell Culture System That Mimics Chronic Lymphocytic Leukemia 
Cells Microenvironment for Drug Screening and Characterization . . . . . . . . . 217
Alessandro Natoni, Michael O’Dwyer, and Corrado Santocanale
15 Two-Dimensional vs. Three-Dimensional In Vitro Tumor Migration 
and Invasion Assays. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
Miriam Zimmermann, Carol Box, and Suzanne A. Eccles 
16 Tumor Spheroid-Based Migration Assays for Evaluation 
of Therapeutic Agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
Maria Vinci, Carol Box, Miriam Zimmermann, 
and Suzanne A. Eccles 
17 The Neurosphere Assay Applied to Neural Stem Cells 
and Cancer Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
Rossella Galli 
PART VI GENETICALLY ENGINEERED ANIMAL MODELS TO STUDY GENE 
FUNCTIONS
18 Genetically Engineered Animal Models for In Vivo Target 
Identification and Validation in Oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
Gemma Texidó 
19 Target Validation in Mice by Constitutive and Conditional RNAi . . . . . . . . . . 307
Aljoscha Kleinhammer, Wolfgang Wurst, and Ralf Kühn 
20 In Vivo Target Validation by Inducible RNAi in Human 
Xenograft Mouse Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
Marco Mazzoletti and Gemma TexidóContents xi
PART VII TRANSLATIONAL METHODS TO VALIDATE BIOMARKERS
21 Bright-Field In Situ Hybridization Methods to Discover Gene 
Amplifications and Rearrangements in Clinical Samples . . . . . . . . . . . . . . . . . . 341
Hiroaki Nitta and Thomas M. Grogan 
22 Combined MicroRNA In Situ Hybridization and Immunohistochemical 
Detection of Protein Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
Boye Schnack Nielsen and Kim Holmstrøm
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367

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