Medicinal chemistry approaches to personalized medicine /

Medicinal chemistry approaches to personalized medicine /

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Edited by two renowned medicinal chemists who have pioneered the development of personalized therapies in their respective fields, this authoritative analysis of what is already possible is the first of its kind, and the only one to focus on drug development issues. Numerous case studies from the fi...

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Bibliographic Details
Other Authors: Lackey, Karen, Roth, Bruce D
Format: Book
Language:English
Published: Weinheim an der Bergstrasse, Germany : Wiley-VCH, 2014
Series:Methods and principles in medicinal chemistry ; v. 59
Subjects:
Drugs > Synthesis
Pharmaceutical chemistry
Drugs
Electronic books
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490 1 |a Methods and Principles in Medicinal Chemistry ;  |v Volume 59 
504 |a Includes bibliographical references at the end of each chapters and index 
505 0 0 |g 1  |t Medicinal Chemistry Approaches to Creating Targeted Medicines /   |r Bruce D. Roth  |g Roth, Bruce D., Karen Lackey  |g Lackey, Karen  |g 1 --  |g 1.1  |t Introduction  |g 1 --  |g 1.2  |t Role of Medicinal Chemistry in Drug Discovery  |g 2 --  |g 1.3  |t Evolution of Molecular Design for Subsets of Patients  |g 4 --  |g 1.4  |t Combinations for Effective Therapies  |g 6 --  |g 1.5  |t Biomarkers in Targeting Patients  |g 9 --  |g 1.6  |t Emerging Field of Epigenetics  |g 9 --  |g 1.7  |t Systems Chemical Biology  |g 10 --  |g 1.8  |t Theranostics and Designing Drug Delivery Systems  |g 12 --  |g 1.9  |t Rapid Progress in Further Personalizing Medicine Expected  |g 15 --  |t References  |g 18 --  |g 2  |t Discovery of Predictive Biomarkers for Anticancer Drugs /   |r Richard M. Neve  |g Neve, Richard M., Lisa D. Belmont  |g Belmont, Lisa D., Richard Bourgon  |g Bourgon, Richard, Marie Evangelista  |g Evangelista, Marie, Xiaodong Huang  |g Huang, Xiaodong, Maike Schmidt  |g Schmidt, Maike, Robert L. Yauch  |g Yauch, Robert L., Jeffrey Settleman  |g Settleman, Jeffrey  |g 21 --  |g 2.1  |t Introduction  |g 22 --  |g 2.2  |t "Oncogene Addiction" as a Paradigm for Clinical Implementation of Predictive Biomarkers  |g 24 --  |g 2.3  |t Cancer Cell Lines as a Model System for Discovery of Predictive Biomarkers  |g 28 --  |g 2.3.1  |t Historical Application of Cell lines in Cancer Research  |g 28 --  |g 2.3.2  |t Biomarker Discovery Using Cell line Models  |g 29 --  |g 2.3.3  |t Cell Lines as Models of Human Cancer  |g 31 --  |g 2.3.4  |t Challenges and Limitations of Cell Line Models  |g 32 --  |g 2.4  |t Modeling Drug Resistance to Discover Predictive Biomarkers  |g 33 --  |g 2.5  |t Discovery of Predictive Biomarkers in the Context of Treatment Combinations  |g 38 --  |g 2.6  |t Discovery of Predictive Biomarkers for Antiangiogenic Agents  |g 42 --  |g 2.6.1  |t Challenges  |g 43 --  |g 2.6.2  |t Pathway Activity as a Predictor of Drug Efficacy  |g 44 --  |g 2.6.3  |t Predicting Inherent Resistance  |g 45 --  |g 2.6.4  |t On-Treatment Effects as a Surrogate of Drug Efficacy  |g 45 --  |g 2.6.5  |t Summary  |g 46 --  |g 2.7  |t Gene Expression Signatures as Predictive Biomarkers  |g 47 --  |g 2.7.1  |t Signature Discovery Unsupervised Clustering  |g 47 --  |g 2.7.2  |t Diagnostic Development: Supervised Classification  |g 48 --  |g 2.7.3  |t Summary  |g 50 --  |g 2.8  |t Current Challenges in Discovering Predictive Biomarkers  |g 51 --  |g 2.8.1  |t Access to Tumor Cells Is Limited during Treatment  |g 51 --  |g 2.8.2  |t Drivers and Passengers  |g 53 --  |g 2.8.3  |t Epigenetic Regulation Adds Another Layer of Complexity  |g 54 --  |g 2.8.4  |t Many Oncoproteins and Tumor Suppressors Undergo Regulatory Posttranslational Modifications  |g 55 --  |g 2.9  |t Future Perspective  |g 56 --  |t References  |g 57 --  |g 3  |t Crizotinib /   |r Jean Cui  |g Cui, Jean, Robert S. Kania  |g Kania, Robert S., Martin P. Edwards  |g Edwards, Martin P  |g 71 --  |g 3.1  |t Introduction  |g 71 --  |g 3.2  |t Discovery of Crizotinib (PF-02341066)[40]  |g 74 --  |g 3.3  |t Kinase Selectivity of Crizotinib  |g 77 --  |g 3.4  |t Pharmacology of Crizotinib [45,46]  |g 78 --  |g 3.5  |t Human Clinical Efficacies of Crizotinib  |g 80 --  |g 3.6  |t Summary  |g 83 --  |t References  |g 85 --  |g 4  |t Discovery and Development of Vemurafenib: First-in-Class Inhibitor of Mutant BRAF for the Treatment of Cancer /   |r Prabha Ibrahim  |g Ibrahim, Prabha, Jiazhong Zhang  |g Zhang, Jiazhong, Chao Zhang  |g Zhang, Chao, James Tsai  |g Tsai, James, Gaston Habets  |g Habets, Gaston, Gideon Bollag  |g Bollag, Gideon  |g 91 --  |g 4.1  |t Background  |g 91 --  |g 4.2  |t Discovery and Development of Vemurafenib (PLX4032)  |g 92 --  |g 4.3  |t Pharmacology  |g 95 --  |g 4.4  |t Clinical Efficacy and Safety  |g 96 --  |g 4.5  |t Companion Diagnostic (cobas 4800) Development  |g 96 --  |g 4.6  |t Synthesis  |g 96 --  |g 4.6.1  |t Discovery Route(s)  |g 96 --  |g 4.6.2  |t Process Route  |g 97 --  |g 4.7  |t Summary  |g 98 --  |t References  |g 98 --  |g 5  |t Targeting Basal-Cell Carcinoma: Discovery and Development of Vismodegib (GDC-0449), a First-in-Class Inhibitor of the Hedgehog Pathway /   |r James C. Marsters Jr.  |g Marsters, James C., Jr., Harvey Wong  |g Wong, Harvey  |g 101 --  |g 5.1  |t Introduction  |g 101 --  |g 5.2  |t Hedgehog and Basal-Cell Carcinoma  |g 102 --  |g 5.3  |t Cydopamine as an SMO Antagonist  |g 102 --  |g 5.4  |t Small-Molecule Inhibitors of SMO  |g 103 --  |g 5.5  |t Preclinical Characterization of Vismodegib  |g 107 --  |g 5.5.1  |t Plasma Protein Binding and Blood Plasma Partitioning  |g 207 --  |g 5.5.2  |t In Vitro and Exploratory In Vivo Metabolism of Vismodegib  |g 208 --  |g 5.5.3  |t Drug-Drug Interaction Potential  |g 109 --  |g 5.5.4  |t Preclinical Pharmacokinetics  |g 109 --  |g 5.5.5  |t Predicted Human Pharmacokinetics  |g 110 --  |g 5.5.6  |t Summary  |g 112 --  |g 5.6  |t Vismodegib Clinical Experience in Phase I  |g 112 --  |t References  |g 114 --  |g 6  |t G-Quadruplexes as Therapeutic Targets in Cancer /   |r Stephen Neidle  |g Neidle, Stephen  |g 117 --  |g 6.1  |t Introduction  |g 117 --  |g 6.2  |t Quadruplex Fundamentals  |g 117 --  |g 6.3  |t Genomic Quadruplexes  |g 119 --  |g 6.4  |t Quadruplexes in Human Telomeres  |g 120 --  |g 6.5  |t Quadruplexes as Anticancer Targets - Evidence from In Vivo Studies  |g 123 --  |g 6.6  |t Native Quadruplex Structures  |g 125 --  |g 6.7  |t Quadruplex-Small-Molecule Structures  |g 130 --  |g 6.8  |t Developing Superior Quadruplex-Binding Ligands  |g 130 --  |g 6.9  |t Condusions  |g 134 --  |t References  |g 136 --  |g 7  |t Identifying Actionable Targets in Cancer Patients /   |r David Uehling  |g Uehling, David, Janet Dancey  |g Dancey, Janet, Andrew M.K. Brown  |g Brown, Andrew M.K., John McPherson  |g McPherson, John, Rima Al-awar  |g Al-awar, Rima  |g 147 --  |g 7.1  |t Introduction and Background  |g 147 --  |g 7.2  |t Overview of Genomic Sequencing and Its Impact on the Identification of Actionable Mutations  |g 149 --  |g 7.3  |t Actionable Targets by Clinical Molecular Profiling: the OICR/PMH Experience  |g 157 --  |g 7.4  |t Some Experiences of Other Clinical Oncology Molecular Profiling Studies  |g 163 --  |g 7.5  |t Identifying Secondary and Novel Mutations through Molecular Profiling  |g 165 --  |g 7.6  |t Understanding and Targeting Resistance Mutations: a Challenge and an Opportunity for NGS  |g 166 --  |g 7.6.1  |t Identification and Treatment Strategies for Actionable Secondary Resistance Mutations  |g 169 --  |g 7.6.2  |t Toward the Identification of Actionable Primary Resistance Mutations  |g 173 --  |g 7.7  |t Concluding Remarks and Future Perspectives  |g 175 --  |t References  |g 178 --  |g 8  |t DNA Damage Repair Pathways and Synthetic Lethality /   |r Simon Ward  |g Ward, Simon  |g 183 --  |g 8.1  |t Introduction  |g 183 --  |g 8.2  |t DNA Damage Response  |g 184 --  |g 8.3  |t Synthetic Lethality  |g 185 --  |g 8.4  |t Lead Case Study PARP Inhibitors  |g 188 --  |g 8.4.1  |t Introduction  |g 188 --  |g 8.4.2  |t Discovery of PARP Inhibitors  |g 189 --  |g 8.4.3  |t Clinical Development of PARP Inhibitors  |g 190 --  |g 8.4.4  |t Future for PARP Inhibitors  |g 192 --  |g 8.5  |t Additional Case Studies  |g 194 --  |g 8.5.1  |t MLH1/MSH2  |g 194 --  |g 8.5.2  |t p53-ATM  |g 197 --  |g 8.5.3  |t Chkl-DNA Repair  |g 197 --  |g 8.5.4  |t DNA-PK-mTOR  |g 197 --  |g 8.5.5  |t DNA Ligases  |g 198 --  |g 8.5.6  |t WEE1  |g 198 --  |g 8.5.7  |t APE1  |g 198 --  |g 8.5.8  |t MGMT  |g 199 --  |g 8.5.9  |t RAD51  |g 199 --  |g 8.6  |t Screening for Synthetic Lethality  |g 199 --  |g 8.6.1  |t RAS  |g 202 --  |g 8.6.2  |t VHL  |g 202 --  |g 8.6.3  |t MRN  |g 203 --  |g 8.7  |t Contextual Synthetic Lethality Screening  |g 203 --  |g 8.8  |t Cancer Stem Cells  |g 204 --  |g 8.9  |t Conclusions and Future Directions  |g 204 --  |t References  |g 205 --  |g 9  |t Amyloid Chemical Probes and Theranostics: Steps Toward Personalized Medicine in Neurodegenerative Diseases /   |r Maria Laura Bolognesi  |g Bolognesi, Maria Laura  |g 211 --  |g 9.1  |t Introduction  |g 211 --  |g 9.2  |t Amyloid Plaques as the Biomarker in AD  |g 212 --  |g 9.3  |t Detecting Amyloid Plaques in Patients: from Alois Alzheimer to Amyvid and Beyond  |g 214 --  |g 9.4  |t Same Causes, Same Imaging Agents?  |g 218 --  |g 9.5  |t Theranostics in AD  |g 219 --  |g 9.6  |t Conclusions and Perspectives  |g 220 --  |t References  |g 222 --  |g 10  |t From Human Genetics to Drug Candidates: An Industrial Perspective on LRRK2 Inhibition as a Treatment for Parkinson's Disease /   |r Haitao Zhu  |g Zhu, Haitao, Huifen Chen  |g Chen, Huifen, William Cho  |g Cho, William, Anthony A. Estrada  |g Estrada, Anthony A., Zachary K. Sweeney  |g Sweeney, Zachary K.  |g 227 --  |g 10.1  |t Introduction  |g 227 --  |g 10.2  |t Biochemical Studies of LRRK2 Function  |g 229 --  |g 10.3  |t Cellular Studies of LRRK2 Function  |g 230 --  |g 10.4  |t Animal Models of LRRK2 Function  |g 233 --  |g 10.5  |t Clinical Studies of LRRK2-Associated PD and Future Prospects  |g 234 --  |g 10.6  |t Small-Molecule Inhibitors of LRRK2  |g 236 --  |g 10.7  |t Structural Models of the LRRK2 Kinase Domain  |g 237 --  |g 10.8  |t Strategies Used to Identify LRRK2 Kinase Inhibitors (Overview)  |g 238 --  |g 10.9  |t Conclusions  |g 246 --  |t References  |g 247 --  |g 11  |t Therapeutic Potential of Kinases in Asthma /   |r Dramane Lainé  |g Lainé, Dramane, Matthew Lucas  |g Lucas, Matthew, Francisco Lopez-Tapia  |g Lopez-Tapia, Francisco, Stephen Lynch  |g Lynch, Stephen  |g 255 --  |g 11.1  |t Introduction  |g 255 --  |g 11.2  |t Mitogen-Activated Protein Kinases  |g 256 --  |g 11.2.1  |t p38  |g 257 --  |g 11.2.2  |t JNK  |g 259 --  |g 11.2.3  |t ERK  |g 260 --  |g 11.3  |t Nonreceptor Protein Tyrosine Kinases  |g 261 --  |g 11.3.1  |t Syk  |g 261 --  |g 11.3.2  |t Lck  |g 263 --  |g 11.3.3  |t JAK  |g 264 --  |g 11.3.4  |t ITK  |g 265 --  |g 11.3.5  |t Btk  |g 266 --  |g 11.4  |t Receptor Tyrosine Kinases  |g 266 --  |g 11.4.1  |t EGFR  |g 267 --  |g 11.4.2  |t c-Kit  |g 268 --  |g 11.4.3  |t PDGFR  |g 269 --  |g 11.4.4  |t VEGFR  |g 270 --  |g 11.5  |t Phosphatidylinositol-3 Kinases  |g 270 --  |g 11.6  |t AGC Kinases  |g 272 --  |g 11.6.1  |t PKC  |g 272 --  |g 11.6.2  |t ROCK  |g 273 --  |g 11.7  |t IkB Kinase  |g 275 --  |g 11.8  |t Other Kinases  |g 276 --  |g 11.8.1  |t SphK  |g 276 --  |g 11.8.2  |t GSK-3β  |g 277 --  |g 11.9  |t Conclusions: Future Directions  |g 278 -- 
505 8 0 |t References  |g 279 --  |g 12  |t Developing Targeted PET Tracers in the Era of Personalized Medicine /   |r Sandra M. Sanabria Bohorquez  |g Bohorquez, Sandra M. Sanabria, Nicholas van Bruggen  |g Bruggen, Nicholas van, Jan Marik  |g Marik, Jan  |g 289 --  |g 12.1  |t Imaging and Pharmacodynamics Biomarkers in Drug Development  |g 289 --  |g 12.2  |t General Considerations for Development of ¹¹C- and ¹⁸F-labeled PET Tracers  |g 292 --  |g 12.3  |t Radiolabeling Compounds with ¹¹C  |g 294 --  |g 12.3.1  |t Preparation of ¹¹C and Basic Reactive Intermediates  |g 294 --  |g 12.3.2  |t ¹¹C-Methylations, Formation of ¹¹C-X Bond (X= O, N, S)  |g 295 --  |g 12.3.3  |t ¹¹C-Methylations, Formation of ¹¹C-C Bond  |g 297 --  |g 12.3.4  |t Reactions with ¹¹CO₂  |g 299 --  |g 12.3.5  |t Reactions with ¹¹CO  |g 301 --  |g 12.3.6  |t Reactions with H¹¹ CN  |g 303 --  |g 12.4  |t Radiolabeling Compounds with ¹⁸F  |g 304 --  |g 12.4.1  |t Formation of C-¹⁸F Bond, Nucleophilic Substitutions  |g 304 --  |g 12.4.2  |t Aliphatic Nudeophilic ¹⁸F-Fluorination  |g 306 --  |g 12.4.3  |t Aromatic Nucleophilic ¹⁸F-Fluorination  |g 309 --  |g 12.4.4  |t Elertrophilic ¹⁸F-Fluorination  |g 313 --  |g 12.4.5  |t Formation of ¹⁸F-Al, Si, B Bond  |g 314 --  |g 12.5  |t PET Imaging in the Clinic, Research, and Drug Development  |g 315 --  |g 12.5.1  |t PET in Oncology  |g 315 --  |g 12.5.2  |t PET Neuroimaging  |g 317 --  |g 12.5.3  |t PET in Cardiology  |g 319 --  |g 12.6  |t PET Tracer Kinetic Modeling for Quantification of Tracer Uptake  |g 320 --  |g 12.7  |t Concluding Remarks  |g 325 --  |t References  |g 325 --  |g 13  |t Medicinal Chemistry in the Context of the Human Genome /   |r Andreas Brunschweiger  |g Brunschweiger, Andreas, Jonathan Hall  |g Hall, Jonathan  |g 343 --  |g 13.1  |t Introduction  |g 343 --  |g 13.2  |t Drugs Targeting Kinases  |g 344 --  |g 13.3  |t Drugs Targeting Phosphatases  |g 347 --  |g 13.4  |t In silico-Based Lead Discovery in the GPCR Family  |g 348 --  |g 13.5  |t Targeting Epigenetic Regulation: Histone Demethylases  |g 350 --  |g 13.6  |t Targeting Epigenetic Regulation: Histone Deacetylases  |g 351 --  |g 13.7  |t A Family-Wide Approach to Poly(ADP-Ribose) Polymerases  |g 352 --  |g 13.8  |t Future Drug Target Superfamilies: Ubiquitinanon and Deubiquitination  |g 353 --  |g 13.9  |t Summary and Outlook  |g 354 --  |t References  |g 355 
506 |a Access restricted by licensing agreement 
506 |a Restricted for use by site license 
520 |a Edited by two renowned medicinal chemists who have pioneered the development of personalized therapies in their respective fields, this authoritative analysis of what is already possible is the first of its kind, and the only one to focus on drug development issues. Numerous case studies from the first generation of "personalized drugs" are presented, highlighting the challenges and opportunities for pharmaceutical development. While the majority of these examples are taken from the field of cancer treatment, other key emerging areas, such as neurosciences and inflammation, are also covered. With its careful balance of current and future approaches, this handbook is a prime knowledge source for every drug developer, and one that will remain up to date for some time to come. From the content: Discovery of Predictive Biomarkers for Anticancer Drugs, Discovery and Development of Vemurafenib, Targeting Basal-Cell Carcinoma, G-Quadruplexes as Therapeutic Targets in Cancer, From Human Genetics to Drug Candidates: An Industrial Perspective on LRRK2 Inhibition as a Treatment for Parkinson's Disease, Therapeutic Potential of Kinases in Asthma, DNA Damage Repair Pathways and Synthetic Lethality, Medicinal Chemistry in the Context of the Human Genome, and many more. Book jacket 
588 |a Description based on online resource; title from PDF title page (ebrary, viewed December 11, 2013) 
590 |a Access is available to the Yale community 
590 |a Electronic reproduction. Palo Alto, Calif. : ebrary, 2013. Available via World Wide Web. Access may be limited to ebrary affiliated libraries 
650 0 |a Drugs  |x Synthesis 
650 0 |a Pharmaceutical chemistry 
650 7 |a Drugs  |2 fast 
650 7 |a Drugs  |x Synthesis  |2 fast 
650 7 |a Pharmaceutical chemistry  |2 fast 
655 0 |a Electronic books 
700 1 |a Lackey, Karen 
700 1 |a Roth, Bruce D 
776 0 8 |i Print version:  |t Medicinal chemistry approaches to personalized medicine  |d Weinheim an der Bergstrasse, Germany : Wiley-VCH, c2014   |h xxvii, 377 pages   |k Methods and principles in medicinal chemistry ; Volume 59.  |z 9783527333943 
776 0 8 |i Print version:  |t Medicinal chemistry approaches to personalized medicine  |d Weinheim an der Bergstrasse, Germany : Wiley-VCH, c2014  |h xxvii, 377 pages  |k Methods and principles in medicinal chemistry ; Volume 59.  |z 9783527333943 
797 2 |a ebrary 
830 0 |a Methods and principles in medicinal chemistry ;  |v v. 59 
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