About the editor ................................................ x
Contributors ................................................... xi
Introduction .................................................. xiv
PART I: BASIC PRINCIPLES ........................................ 1
1. Modern cancer drug discovery: integrating targets,
technologies and treatments .................................. 3
Paul Workman and Ian Collins
1.1. Introduction: changing times ............................ 3
1.2. Successes and limitations ............................... 4
1.3. Integrated small-molecule drug discovery and
development ............................................ 10
1.4. New molecular targets: the "druggable" cancer genome ... 10
1.5. From drug target to development candidate .............. 16
1.6. Examples of case histories for molecularly targeted
cancer therapeutics .................................... 24
1.7. Biomarkers, the pharmacological audit trail and
clinical development ................................... 26
1.8. Conclusions and outlook: towards individualized
molecular cancer medicine .............................. 29
References .................................................. 33
2. Preclinical pharmacology and in vivo models ................. 39
Lloyd Kelland
2.1. Introduction ........................................... 39
2.2. Contemporary preclinical cancer drug discovery ......... 40
2.3. In vitro pharmacological evaluation .................... 41
2.4. Information gained from in vitro cell lines ............ 42
2.5. In vivo pharmacokinetics (PK) and pharmacodynamics
(PD): continuing the pharmacological audit trail ....... 43
2.6. In vivo anti-tumor models: choice and
predictiveness? ........................................ 45
2.7. Concluding remarks ..................................... 50
References .................................................. 51
3. Clinical trial designs for more rapid proof-of-principle
and approval ................................................ 53
Mitesh J. Borad and Daniel D. Von Hoff
3.1. Introduction ........................................... 53
3.2. NDA plan at the time of IND ............................ 54
3.3. Phase I trial design innovations ....................... 54
3.4. Concept of a continuous Phase I ........................ 59
3.5. Phase II trial design innovations ...................... 60
3.6. Phase III trial design innovations (enrichment
designs) ............................................... 67
3.7. Other approaches to enrich trial populations ........... 72
3.8. Innovations in design and selection of endpoints ....... 73
3.9. Regulatory strategies .................................. 77
3.10.Other approaches to accelerate drug development ........ 78
3.11.New perspectives ....................................... 79
3.12.Summary ................................................ 81
References .................................................. 83
PART II METHODOLOGY ............................................ 89
4. Structural biology and anticancer drug design ............... 91
Dominic Tisi, Gianni Chessari, Andrew J. Woodhead
and Harren Jhoti
4.1. Introduction ........................................... 91
4.2. High-throughput X-ray crystallography .................. 93
4.3. Structural biology and structure-based drug design ..... 95
4.4. Fragment screening using X-ray crystallography ......... 97
4.5. Case history: cyclin-dependent kinase inhibitors,
from fragment hit to clinical candidate ................ 98
4.6. Compound profiling .................................... 102
4.7. Conclusions ........................................... 104
References ................................................. 105
5. Natural product chemistry and anticancer drug discovery .... 107
Donna M. Huryn and Peter Wipf
5.1. Introduction .......................................... 107
5.2. Exemestane (aromasin) ................................. 108
5.3. Fulvestrant/faslodex .................................. 109
5.4. Flavonoids ............................................ 110
5.5. Bexarotene (targretin) ................................ 111
5.6. Epothilones ........................................... 112
5.7. Maytansine ............................................ 114
5.8. Geldanamycin .......................................... 115
5.9. UCN-01 ................................................ 116
5.10.Camptothecin .......................................... 117
5.11.Prodigiosin ........................................... 118
5.12.Azacitidine ........................................... 119
5.13.FK-288 ................................................ 121
5.14.Hemiasterlin .......................................... 122
5.15.Calicheamicin ......................................... 124
5.16.Conclusion ............................................ 126
References ................................................. 126
6. Pharmacokinetics and ADME optimization in drug discovery ... 131
Chad L. Stoner, Matthew D. Troutman and Caroline
E. Laverty
6.1. Introduction .......................................... 131
6.2. Absorption ............................................ 133
6.3. Distribution .......................................... 140
6.4. Metabolism ............................................ 142
6.5. Elimination ........................................... 145
6.6. Biochemical barriers to drug therapy: efflux
transporters .......................................... 145
6.7. Induction ............................................. 147
6.8. Conclusions ........................................... 148
PART III DRUGS IN THE CLINIC .................................. 155
7. Temozolomide: from cytotoxic to molecularly-targeted
agent ...................................................... 157
Malcolm F.G. Stevens
7.1. Introduction .......................................... 157
7.2. Towards imidazotetrazines and azolastone
(mitozolomide) ........................................ 158
7.3. From mitozolomide to temozolomide ..................... 160
7.4. Synthesis and chemistry of temozolomide ............... 161
7.5. Early clinical trials on temozolomide ................. 163
7.6. Mode of action of temozolomide ........................ 163
7.7. Epigenetic silencing of the MGMT gene ................. 167
7.8. New analogs of temozolomide ........................... 167
7.9. Summary: temozolomide, targets, molecular targets
and validated targets ................................. 168
References ................................................. 169
8. Camptothecins for drug design, cancer cell death and
gene targeting ............................................. 173
Jerome Kluza, Paola B. Arimondo, Marie-Helene
David-Cordonnier and Christian Bailly
8.1. Introduction .......................................... 173
8.2. Camptothecins: molecular clamps for the
topoisomerase I-DNA complex ........................... 174
8.3. Design of CPT derivatives: an endless series .......... 177
8.4. From trapped-topoisomerase I to DNA double strand
breaks ................................................ 182
8.5. DN A repair or cell death ............................. 183
8.6. Sequence-specific targeting of topoisomerase-
mediated DNA cleavage ................................. 186
8.7. Structure-activity relationships ...................... 188
8.8. Applications .......................................... 189
8.9. Conclusion ............................................ 190
References ................................................. 190
9. Targeting thymidylate synthase by antifolate drugs for
the treatment of cancer .................................... 198
Ann L. Jackman, Martin Forster and Matthew Ng
9.1. Introduction .......................................... 198
9.2. Thymidylate synthase as an anti-cancer drug target .... 199
9.3. CB3717 ................................................ 200
9.4. Raltitrexed ........................................... 202
9.5. Pemetrexed ............................................ 207
9.6. Plevitrexed ........................................... 210
9.7. BGC945 ................................................ 214
9.8. Conclusions ........................................... 218
References ................................................. 219
PART IV: NEW AGENTS ........................................... 227
10.Targeting inactive kinases: structure as a foundation
for cancer drug discovery .................................. 229
David J. Hosfield and Clifford D. Mol
10.1.Introduction .......................................... 229
10.2.c-Kit, a Type III receptor protein tyrosine kinase .... 230
10.3.c-Abl, a cellular protein tyrosine kinase ............. 239
10.4.b-Raf-Bay43-9006 co-crystal structure ................. 244
10.5.P38-BIRB-796 co-crystal structure ..................... 245
10.6.VEGF-R2-4-amino-furopyrimidine co-crystal structure ... 246
10.7.Conclusions and perspectives .......................... 249
References ................................................. 250
11.Cell cycle inhibitors in cancer: current status and
future directions .......................................... 253
Peter M. Fischer
11.1.Introduction .......................................... 253
11.2.The G1-S nexus ........................................ 255
11.3.The DN A replication and damage checkpoints ........... 260
11.4.Mitosis ............................................... 266
11.5.Conclusion ............................................ 278
References ................................................. 279
12.Inhibition of DNA repair as a therapeutic target ........... 284
Nicola J. Curtin and Thomas Helleday
12.1.Introduction .......................................... 284
12.2.06-Alkylguanine DNA alkyltransferase (AGT) ............ 286
12.3.Poly(ADP-ribose) polymerase (PARP) .................... 289
12.4.DNA-dependent protein kinase (DNA-PK) ................. 295
12.5.Exploiting synthetic lethality for cancer
treatments ............................................ 297
12.6.Summary and conclusions ............................... 300
References ................................................. 300
13.HSP90 inhibitors: targeting the cancer chaperone for
combinatorial blockade of oncogenic pathways ............... 305
Swee Y. Sharp, Keith Jones and Paul Workman
13.1.Introduction .......................................... 305
13.2.Classes of HSP90 inhibitors ........................... 310
13.3.Summary and future perspectives ....................... 326
References ................................................. 329
14.Heat shock protein-90 directed therapeutics and target
validation ................................................. 336
Edward A. Sausville
14.1.Introduction .......................................... 336
14.2.Overview of heat shock protein function ............... 337
14.3.Benzoquinoid ansamycin HSP90 antagonists .............. 339
14.4.Radicicol (monorden) .................................. 343
14.5.Radester, radamide, and radanamycin ................... 344
14.6.Purine scaffold inhibitors: PU3 and analogs ........... 344
14.7.Pyrazole resorcinols .................................. 344
14.8.Shepherdin-related structures ......................... 345
14.9.Novobiocin and analogs ................................ 346
14.10.Conclusion and perspectives .......................... 347
References ................................................. 347
15.Inhibitors of tumor angiogenesis ........................... 351
Adrian L. Harris and Daniele G.Generali
15.1.Introduction: overview of tumor angiogenesis .......... 351
15.2.Tumor angiogenesis: assessment approaches ............. 353
15.3.Tumor angiogenesis-related pathways and anti-
angiogenic drug
15.4.Conclusions and future directions ..................... 373
References ................................................. 374
16.The biology and oncology of RAF-ERK signaling .............. 382
Victoria Emuss and Richard Marais
16.1.Introduction .......................................... 382
16.2.MAP kinase pathways ................................... 383
16.3.Outcomes of ERK signaling ............................. 384
16.4.RAF proteins .......................................... 385
16.5.ERK signaling and cancer .............................. 390
16.6.Therapeutic opportunities ............................. 392
16.7.Conclusions ........................................... 396
References ................................................. 397
PART V THE REALITY OF CANCER DRUGS IN THE CLINIC
17.Cancer drug resistance ..................................... 405
V. Karavasilis, A. Reid, R. Sinha and J.S. de Bono
17.1.Introduction .......................................... 405
17.2.Drug resistance in conventional chemotherapy .......... 406
17.3.Targeted therapeutics ................................. 410
17.4.Conclusions: overcoming resistance to TKI inhibitors .. 420
References ................................................. 422
18.Failure modes in anticancer drug discovery and
development ................................................ 424
Homer L. Pearce, Kerry L. Blanchard and Christopher
A. Slapak
18.1.Introduction .......................................... 424
18.2.Failure modes in the discovery process ................ 425
18.3.Failure modes in clinical development ................. 430
18.4.Conclusions ........................................... 433
References ................................................. 434
Glossary ...................................................... 436
Index ......................................................... 440
|
