Medicinal chemistry approaches to personalized medicine:
Saved in:
| Format: | Book |
|---|---|
| Language: | English |
| Published: |
Weinheim
Wiley-VCH
2014
|
| Series: | Methods and principles in medicinal chemistry
59 |
| Subjects: | |
| Online Access: | Inhaltsverzeichnis Inhaltstext Inhaltsverzeichnis Inhaltsverzeichnis |
| Item Description: | Literaturangaben |
| Physical Description: | XXVII, 377 S. Ill., graph. Darst. 25 cm |
| ISBN: | 3527333940 9783527333943 9783527677276 |
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Record in the Search Index
| _version_ | 1823026388037271552 |
|---|---|
| adam_text |
V
CONTENTS
LIST OF
CONTRIBUTORS XI
FOREWORD XV
PREFACE XIX
A PERSONAL FOREWORD XXI
ACRONYMS
XXIII
1
MEDICINAL CHEMISTRY APPROACHES TO CREATING TARGETED MEDICINES 1
BRUCE D. ROTH AND KAREN LACKEY
1.1 INTRODUCTION 1
1.2
ROLE OF MEDICINAL CHEMISTRY IN DRUG DISCOVERY 2
1.3 EVOLUTION OF MOLECULAR DESIGN FOR SUBSETS OF PATIENTS 4
1.4 COMBINATIONS FOR EFFECTIVE THERAPIES 6
1.5 BIOMARKERS IN TARGETING PATIENTS 9
1.6 EMERGING FIELD OF EPIGENETICS 9
1.7 SYSTEMS CHEMICAL BIOLOGY 10
1.8
THERANOSTICS AND DESIGNING DRUG DELIVERY SYSTEMS 12
1.9 RAPID PROGRESS IN FURTHER PERSONALIZING MEDICINE EXPECTED 15
REFERENCES 18
2
DISCOVERY OF PREDICTIVE BIOMARKERS FOR ANTICANCER DRUGS 21
RICHARD M. NEVE, LISA D. BELMONT, RICHARD BOURGON, MARIE EVANGELISTA,
XIAODONG HUANG, MAIKE SCHMIDT, ROBERT L. YAUCH, AND JEFFREY SETTLEMAN
2.1 INTRODUCTION 21
2.2
"ONCOGENE ADDICTION" AS A PARADIGM FOR CLINICAL IMPLEMENTATION
OF PREDICTIVE BIOMARKERS 24
2.3 CANCER CELL LINES AS A MODEL SYSTEM FOR DISCOVERY OF PREDICTIVE
BIOMARKERS 28
2.3.1
HISTORICAL APPLICATION OF CELL LINES IN CANCER RESEARCH 28
2.3.2 BIOMARKER DISCOVERY USING CELL LINE MODELS 29
2.3.3 CELL LINES AS MODELS OF HUMAN CANCER 31
2.3.4 CHALLENGES AND LIMITATIONS OF CELL LINE MODELS 32
2.4
MODELING DRUG RESISTANCE TO DISCOVER PREDICTIVE BIOMARKERS 33
HTTP://D-NB.INFO/1036281132
VI
I CONTENTS
2.5
DISCOVERY OF PREDICTIVE BIOMARKERS IN THE CONTEXT OF TREATMENT
COMBINATIONS 38
2.6 DISCOVERY OF PREDICTIVE BIOMARKERS FOR ANTIANGIOGENIC AGENTS 42
2.6.1 CHALLENGES 43
2.6.2
PATHWAY ACTIVITY AS A PREDICTOR OF DRUG EFFICACY 44
2.6.3 PREDICTING INHERENT RESISTANCE 45
2.6.4 ON-TREATMENT EFFECTS AS A SURROGATE OF DRUG EFFICACY 45
2.6.5 SUMMARY 46
2.7
GENE EXPRESSION SIGNATURES AS PREDICTIVE BIOMARKERS 47
2.7.1 SIGNATURE DISCOVERY; UNSUPERVISED CLUSTERING 47
2.7.2 DIAGNOSTIC DEVELOPMENT: SUPERVISED CLASSIFICATION 48
2.7.3 SUMMARY 50
2.8
CURRENT CHALLENGES IN DISCOVERING PREDICTIVE BIOMARKERS 51
2.8.1 ACCESS TO TUMOR CELLS IS LIMITED DURING TREATMENT 51
2.8.2 DRIVERS AND PASSENGERS 53
2.8.3 EPIGENETIC REGULATION ADDS ANOTHER LAYER OF COMPLEXITY 54
2.8.4 MANY ONCOPROTEINS AND TUMOR SUPPRESSORS UNDERGO REGULATORY
POSTTRANSLATIONAL MODIFICATIONS
55
2.9 FUTURE PERSPECTIVE 56
REFERENCES
57
3
CRIZOTINIB 71
JEAN CUI, ROBERT
S. KANIA, AND MARTIN P. EDWARDS
3.1 INTRODUCTION 71
3.2
DISCOVERY OF CRIZOTINIB (PF-02341066) [40] 74
3.3 KINASE SELECTIVITY OF CRIZOTINIB 77
3.4 PHARMACOLOGY OF CRIZOTINIB [45,46] 78
3.5 HUMAN CLINICAL EFFICACIES OF CRIZOTINIB 80
3.6 SUMMARY 83
REFERENCES
85
4
DISCOVERY AND DEVELOPMENT OF VEMURAFENIB: FIRST-IN-CLASS
INHIBITOR OF MUTANT BRAF FOR THE TREATMENT OF CANCER 92
PRABHA IBRAHIM, JIAZHONG ZHANG, CHAO ZHANG, JAMES TSAI,
CASTON HABETS, AND GIDEON BOLLAG
4.1 BACKGROUND 91
4.2
DISCOVERY AND DEVELOPMENT OF VEMURAFENIB (PLX4032) 92
4.3 PHARMACOLOGY 95
4.4
CLINICAL EFFICACY AND SAFETY 96
4.5 COMPANION DIAGNOSTIC (COBAS 4800) DEVELOPMENT 96
4.6 SYNTHESIS 96
4.6.1
DISCOVERY ROUTE(S) 96
4.6.2 PROCESS ROUTE 97
4.7
SUMMARY 98
REFERENCES
98
CONTENTS
IVII
5
TARGETING BASAL-CELL CARCINOMA: DISCOVERY AND DEVELOPMENT
OFVISMODEGIB (GDC-0449), A FIRST-IN-CLASS INHIBITOR
OF THE HEDGEHOG PATHWAY 101
JAMES C. MARSTERS JR. AND HARVEY WONG
5.1 INTRODUCTION 101
5.2
HEDGEHOG AND BASAL-CELL CARCINOMA 102
5.3 CYCLOPAMINE AS AN SMO ANTAGONIST 102
5.4 SMALL-MOLECULE INHIBITORS OF SMO 103
5.5 PRECLINICAL CHARACTERIZATION OF VISMODEGIB 107
5.5.1 PLASMA PROTEIN BINDING AND BLOOD PLASMA PARTITIONING 107
5.5.2 IN VITRO AND EXPLORATORY IN VIVO METABOLISM OFVISMODEGIB 108
5.5.3 DRUG-DRUG INTERACTION POTENTIAL 109
5.5.4 PRECLINICAL PHARMACOKINETICS 109
5.5.5 PREDICTED HUMAN PHARMACOKINETICS 110
5.5.6 SUMMARY 112
5.6
VISMODEGIB CLINICAL EXPERIENCE IN PHASE I 112
REFERENCES 114
6
G-QUADRUPLEXES AS THERAPEUTIC TARGETS IN CANCER 117
STEPHEN NEIDLE
6.1 INTRODUCTION 117
6.2
QUADRUPLEX FUNDAMENTALS 117
6.3 GENOMIC QUADRUPLEXES 119
6.4 QUADRUPLEXES IN HUMAN TELOMERES 120
6.5 QUADRUPLEXES AS ANTICANCER TARGETS - EVIDENCE FROM IN VIVO STUDIES
123
6.6 NATIVE QUADRUPLEX STRUCTURES 125
6.7
QUADRUPLEX-SMALL-MOLECULE STRUCTURES 130
6.8 DEVELOPING SUPERIOR QUADRUPLEX-BINDING LIGANDS 130
6.9 CONCLUSIONS 134
REFERENCES
136
7
IDENTIFYING ACTIONABLE TARGETS IN CANCER PATIENTS 147
DAVID UEHLING, JANET DANCEY, ANDREW M.K. BROWN, JOHN MCPHERSON,
AND RIMA AL-AWAR
7.1 INTRODUCTION AND BACKGROUND 147
7.2 OVERVIEW OF GENOMIC SEQUENCING AND ITS IMPACT ON THE
IDENTIFICATION OF ACTIONABLE MUTATIONS
149
7.3 ACTIONABLE TARGETS BY CLINICAL MOLECULAR PROFILING: THE OICR/PMH
EXPERIENCE 157
7.4 SOME EXPERIENCES OF OTHER CLINICAL ONCOLOGY MOLECULAR PROFILING
STUDIES
163
7.5
IDENTIFYING SECONDARY AND NOVEL MUTATIONS THROUGH MOLECULAR
PROFILING 165
7.6 UNDERSTANDING AND TARGETING RESISTANCE MUTATIONS: A CHALLENGE
AND AN OPPORTUNITY FOR NGS 166
VIII
| CONTENTS
7.6.1
IDENTIFICATION AND TREATMENT STRATEGIES FOR ACTIONABLE SECONDARY
RESISTANCE MUTATIONS 169
7.6.2 TOWARD THE IDENTIFICATION OF ACTIONABLE PRIMARY RESISTANCE
MUTATIONS 173
7.7 CONCLUDING REMARKS AND FUTURE PERSPECTIVES 175
REFERENCES
178
8
DNA DAMAGE REPAIR PATHWAYS AND SYNTHETIC LETHALITY 183
SIMON WARD
8.1 INTRODUCTION 183
8.2
DNA DAMAGE RESPONSE 184
8.3 SYNTHETIC LETHALITY 185
8.4
LEAD CASE STUDY: PARP INHIBITORS 188
8.4.1 INTRODUCTION 188
8.4.2 DISCOVERY OF PARP INHIBITORS 189
8.4.3 CLINICAL DEVELOPMENT OF PARP INHIBITORS 190
8.4.4
FUTURE FOR PARP INHIBITORS 192
8.5 ADDITIONAL CASE STUDIES 194
8.5.1 MLH1/MSH2 194
8.5.2 P53-ATM 197
8.5.3
CHKL-DNA REPAIR 197
8.5.4 DNA-PK - MTOR 197
8.5.5 DNALIGASES 198
8.5.6 WEE1 198
8.5.7
APE1 198
8.5.8
MGMT 199
8.5.9
RAD51 19 9
8.6
SCREENING FOR SYNTHETIC LETHALITY 199
8.6.1 RAS 202
8.6.2
VHL 202
8.6.3
MRN 203
8.7
CONTEXTUAL SYNTHETIC LETHALITY SCREENING 203
8.8 CANCER STEM CELLS 204
8.9
CONCLUSIONS AND FUTURE DIRECTIONS 204
REFERENCES 205
9
AMYLOID CHEMICAL PROBES AND THERANOSTICS: STEPS TOWARD
PERSONALIZED MEDICINE IN NEURODEGENERATIVE DISEASES 211
MARIA LAURA BOLOGRTESI
9.1 INTRODUCTION 211
9.2
AMYLOID PLAQUES AS THE BIOMARKER IN AD 212
9.3 DETECTING AMYLOID PLAQUES IN PATIENTS: FROM ALOIS ALZHEIMER TO
AMYVID AND BEYOND 214
9.4 SAME CAUSES, SAME IMAGING AGENTS? 218
9.5
THERANOSTICS IN AD 219
CONTENTS
| IX
9.6
CONCLUSIONS AND PERSPECTIVES 220
REFERENCES 222
10
FROM HUMAN GENETICS TO DRUG CANDIDATES: AN INDUSTRIAL PERSPECTIVE
ON LRRK2 INHIBITION AS A TREATMENT FOR PARKINSON'S DISEASE 227
HAITAO ZHU, HUIFEN CHEN, WILLIAM CHO, ANTHONY A. ESTRADA, AND
ZACHARY K. SWEENEY
10.1 INTRODUCTION 227
10.2
BIOCHEMICAL STUDIES OF LRRK2 FUNCTION 229
10.3 CELLULAR STUDIES OF LRRK2 FUNCTION 230
10.4 ANIMAL MODELS OF LRRK2 FUNCTION 233
10.5
CLINICAL STUDIES OF LRRK2-ASSOCIATED PD AND FUTURE PROSPECTS 234
10.6 SMALL-MOLECULE INHIBITORS OF LRRK2 236
10.7 STRUCTURAL MODELS OF THE LRRK2 KINASE DOMAIN 237
10.8 STRATEGIES USED TO IDENTIFY LRRK2 KINASE INHIBITORS (OVERVIEW) 238
10.9
CONCLUSIONS 246
REFERENCES
247
11
THERAPEUTIC POTENTIAL OF KINASES IN ASTHMA 255
DRAMANE LAINE, MATTHEW LUCAS, FRANCISCO LOPEZ-TAPIA, AND STEPHEN
LYNCH
11.1 INTRODUCTION 255
11.2
MITOGEN-ACTIVATED PROTEIN KINASES- 2
11.2.1
P38 257
11.2.2
JNK 259
11.2.3
ERK 260
11.3
NONRECEPTOR PROTEIN TYROSINE KINASES
11.3.1 SYK 261
11.3.2
LCK 263
11.3.3
JAK 264
11.3.4
ITK 265
11.3.5
BTK 266
11.4
RECEPTOR TYROSINE KINASES 266
11.4.1
EGFR 267
11.4.2
C-KIT 268
11.4.3
PDGFR 269
11.4.4
VEGFR 270
11.5
PHOSPHATIDYLINOSITOL-3 KINASES 270
11.6 AGC KINASES 272
11.6.1
PKC 272
11.6.2
ROCK 273
11.7
IKB
KINASE 275
11.8
OTHER KINASES 276
11.8.1
SPHK 276
11.8.2
GSK-3P 277
11.9
CONCLUSIONS: FUTURE DIRECTIONS 278
REFERENCES 279
X
| CONTENTS
12
DEVELOPING TARGETED PET TRACERS IN THE ERA OF PERSONALIZED
MEDICINE 289
SANDRA M. SANABRIA BOHORQUEZ, NICHOLAS VAN BRUGGEN, AND JAN MARIK
12.1 IMAGING AND PHARMACODYNAMICS BIOMARKERS IN DRUG
DEVELOPMENT
289
12.2
GENERAL CONSIDERATIONS FOR DEVELOPMENT OF
N
C- AND
1S
F-IABELED PET
TRACERS 292
12.3
RADIOLABELING COMPOUNDS WITH
11
C 294
12.3.1 PREPARATION OF
U
C AND BASIC REACTIVE INTERMEDIATES 294
12.3.2
N
C-METHYLATIONS, FORMATION OF
N
C-X BOND (X = O, N, S) 295
12.3.3
U
C-METHYLATIONS, FORMATION OF
N
C-C BOND 297
12.3.4 REACTIONS WITH
11
CO2 299
12.3.5 REACTIONS WITH
11
CO 301
12.3.6 REACTIONS WITH H
11
CN 303
12.4
RADIOLABELING COMPOUNDS WITH
1S
F 304
12.4.1 FORMATION OF C-
1S
F BOND, NUDEOPHILIC SUBSTITUTIONS 304
12.4.2 ALIPHATIC NUDEOPHILIC
LS
F-FLUORINATION 306
12.4.3 AROMATIC NUDEOPHILIC
LS
F-FLUORINATION 309
12.4.4 ELECTROPHILIC
LS
F-FLUORINATION 313
12.4.5 FORMATION OF
1S
F-A1, SI, B BOND 314
12.5
PET IMAGING IN THE CLINIC, RESEARCH, AND DRUG DEVELOPMENT 315
12.5.1 PET IN ONCOLOGY 315
12.5.2 PET NEUROIMAGING 317
12.5.3 PET IN CARDIOLOGY 319
12.6 PET TRACER KINETIC MODELING FOR QUANTIFICATION OF TRACER UPTAKE 320
12.7 CONCLUDING REMARKS 325
REFERENCES
325
13
MEDICINAL CHEMISTRY IN THE CONTEXT OF THE HUMAN GENOME 343
ANDREAS BRUNSCHWEIGER AND JONATHAN HALL
13.1 INTRODUCTION 343
13.2
DRUGS TARGETING KINASES 344
13.3 DRUGS TARGETING PHOSPHATASES 347
13.4 IN SIIICO-BASED LEAD DISCOVERY IN THE GPCR FAMILY 348
13.5 TARGETING EPIGENETIC REGULATION: HISTONE DEMETHYLASES 350
13.6 TARGETING EPIGENETIC REGULATION: HISTONE DEACETYLASES 351
13.7
A FAMILY-WIDE APPROACH TO POLY(ADP-RIBOSE) POLYMERASES 352
13.8 FUTURE DRUG TARGET SUPERFAMILIES: UBIQUITINATION AND
DEUBIQUITINATION 353
13.9 SUMMARY AND OUTLOOK 354
REFERENCES
355
INDEX
365 |
| any_adam_object | 1 |
| author_GND | (DE-588)1046595407 |
| building | Verbundindex |
| bvnumber | BV041950234 |
| classification_rvk | VS 5000 |
| ctrlnum | (OCoLC)864497688 (DE-599)DNB1036281132 |
| dewey-full | 615.19 |
| dewey-hundreds | 600 - Technology (Applied sciences) |
| dewey-ones | 615 - Pharmacology and therapeutics |
| dewey-raw | 615.19 |
| dewey-search | 615.19 |
| dewey-sort | 3615.19 |
| dewey-tens | 610 - Medicine and health |
| discipline | Chemie / Pharmazie Medizin |
| format | Book |
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| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-027393212 |
| oclc_num | 864497688 |
| open_access_boolean | |
| owner | DE-19 DE-BY-UBM DE-20 DE-355 DE-BY-UBR |
| owner_facet | DE-19 DE-BY-UBM DE-20 DE-355 DE-BY-UBR |
| physical | XXVII, 377 S. Ill., graph. Darst. 25 cm |
| publishDate | 2014 |
| publishDateSearch | 2014 |
| publishDateSort | 2014 |
| publisher | Wiley-VCH |
| record_format | marc |
| series | Methods and principles in medicinal chemistry |
| series2 | Methods and principles in medicinal chemistry |
| spelling | Medicinal chemistry approaches to personalized medicine ed. by Karen Lackey ... Weinheim Wiley-VCH 2014 XXVII, 377 S. Ill., graph. Darst. 25 cm txt rdacontent n rdamedia nc rdacarrier Methods and principles in medicinal chemistry 59 Literaturangaben Pharmazeutische Chemie (DE-588)4132158-3 gnd rswk-swf (DE-588)4143413-4 Aufsatzsammlung gnd-content Pharmazeutische Chemie (DE-588)4132158-3 s DE-604 Lackey, Karen Sonstige (DE-588)1046595407 oth Methods and principles in medicinal chemistry 59 (DE-604)BV035418617 59 application/pdf http://d-nb.info/1036281132/04 Inhaltsverzeichnis text/html http://deposit.dnb.de/cgi-bin/dokserv?id=4369760&prov=M&dok_var=1&dok_ext=htm Inhaltstext DE-601 pdf/application http://www.gbv.de/dms/bs/toc/750511753.pdf Inhaltsverzeichnis DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=027393212&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Medicinal chemistry approaches to personalized medicine Methods and principles in medicinal chemistry Pharmazeutische Chemie (DE-588)4132158-3 gnd |
| subject_GND | (DE-588)4132158-3 (DE-588)4143413-4 |
| title | Medicinal chemistry approaches to personalized medicine |
| title_auth | Medicinal chemistry approaches to personalized medicine |
| title_exact_search | Medicinal chemistry approaches to personalized medicine |
| title_full | Medicinal chemistry approaches to personalized medicine ed. by Karen Lackey ... |
| title_fullStr | Medicinal chemistry approaches to personalized medicine ed. by Karen Lackey ... |
| title_full_unstemmed | Medicinal chemistry approaches to personalized medicine ed. by Karen Lackey ... |
| title_short | Medicinal chemistry approaches to personalized medicine |
| title_sort | medicinal chemistry approaches to personalized medicine |
| topic | Pharmazeutische Chemie (DE-588)4132158-3 gnd |
| topic_facet | Pharmazeutische Chemie Aufsatzsammlung |
| url | http://d-nb.info/1036281132/04 http://deposit.dnb.de/cgi-bin/dokserv?id=4369760&prov=M&dok_var=1&dok_ext=htm http://www.gbv.de/dms/bs/toc/750511753.pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=027393212&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| volume_link | (DE-604)BV035418617 |
| work_keys_str_mv | AT lackeykaren medicinalchemistryapproachestopersonalizedmedicine |
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