Currently Druggable in Breast Cancer: A Drug Target Competitive Analysis
1 Executive Summary ______ 3
2 About Cancer Highlights __ 5
3 Methodologies __________ 7
4 Table of Contents ________ 9
4.1 List of Figures ___________ 13
4.2 List of Tables ____________ 13
5 How to Use this Report __ 16
6 Breast Cancer Target Localization _________________ 18
7 The Cancer Genome Project and Breast Cancer Targets 25
7.1 Breast Cancer Targets Present in the Cancer Gene Census and in the Catalogue
of Somatic
Mutations in Cancer ____________ 25
8 Protein Expression Profiles of Breast Cancer Drug Targets in Human
_____________ 29
8.1 Expression in Normal Tissues and Cancer Tissues _______ 29
8.2 Expression in Human Cancer Cell Lines and Primary Cells 30
9 Pathway Analysis of Breast Cancer Drugs ___________ 34
10 Protein-Protein Interactions Among Identified Breast Cancer Targets
____________ 77
11 Available Biological Structure Data on Breast Cancer Targets
___________________ 81
12 Drug Target Profiles of Breast Cancer Drugs _________ 84
12.1.1 Catalytic Activity ______________ 85
12.1.2 Cell Adhesion Molecule Activity __ 89
12.1.3 Chaperone Activity ____________ 94
12.1.4 Chemokine Activity ____________ 96
12.1.5 Complement Activity __________ 97
12.1.6 Cysteine-Type Peptidase Activity _ 98
12.1.7 Cytokine Activity _____________ 102
12.1.8 DNA Binding ________________ 107
12.1.9 DNA Repair Protein ___________ 109
12.1.10 DNA Topoisomerase Activity ___ 111
12.1.11 DNA-Directed DNA Polymerase Activity __________________ 113
12.1.12 Glutathione Transferase Activity 114
12.1.13 G-Protein Coupled Receptor Activity _____________________ 115
12.1.14 Growth Factor Activity ________ 118
12.1.15 Hormone Activity ____________ 121
12.1.16 Kinase Activity _______________ 123
12.1.17 Kinase Binding _______________ 130
12.1.18 Kinase Regulator Activity ______ 131
12.1.19 Ligand-Dependent Nuclear Receptor Activity ______________ 133
12.1.20 Ligase Activity _______________ 137
12.1.21 Lipid Kinase Activity __________ 140
12.1.22 Lipid Phosphatase Activity _____ 141
12.1.23 Metallopeptidase Activity ______ 142
12.1.24 Molecular Function Unknown __ 144
12.1.25 Motor Activity _______________ 147
12.1.26 Oxidoreductase Activity _______ 148
12.1.27 Protein Binding ______________ 153
12.1.28 Protein Serine/Threonine Kinase Activity _________________ 154
12.1.29 Protein Threonine/Tyrosine Kinase Activity _______________ 164
12.1.30 Protein-Tyrosine Kinase Activity _ 167
12.1.31 Receptor Activity _____________ 172
12.1.32 Receptor Binding _____________ 180
12.1.33 Receptor Signaling Complex Scaffold Activity ______________ 182
12.1.34 Receptor Signaling Protein Serine/Threonine Kinase Activity__ 185
12.1.35 Serine-Type Peptidase Activity __ 186
12.1.36 Structural Constituent of Cytoskeleton ___________________ 188
12.1.37 Structural Molecule Activity ____ 189
12.1.38 Superoxide Dismutase Activity __ 190
12.1.39 T Cell Receptor Activity ________ 192
12.1.40 Transcription Factor Activity ___ 195
12.1.41 Transcription Regulator Activity _ 208
12.1.42 Transferase Activity __________ 212
12.1.43 Translation Regulator Activity __ 213
12.1.44 Transmembrane Receptor Activity ______________________ 214
12.1.45 Transmembrane Receptor Protein Tyrosine Kinase Activity ___ 216
12.1.46 Transporter Activity __________ 237
13 The Drug-Target Interactome ____________________ 239
14 The Progression and Maturity of Breast Cancer Targets _______________________
244
14.1 Target Profiles of Breast Cancer Drugs in Pre-Registration or on the Market
________ 247
14.2 New and Unique Breast Cancer Targets in Phase III Clinical Development
__________ 248
14.3 New and Unique Breast Cancer Targets in Phase II Clinical Development
___________ 249
14.4 New and Unique Breast Cancer Targets in Phase I Clinical Development
___________ 253
14.5 New and Unique Breast Cancer Targets in Preclinical Development
_______________ 254
14.6 Development Profiles of All Breast Cancer Target Combinations
_________________ 257
15 Targets by Major Therapy Strategies in Breast Cancer 268
15.1 Small Molecules ________ 269
15.1.1 Background _________________ 269
15.1.2 Targets in Breast Cancer _______ 270
15.2 Peptide/Protein Drugs ___ 278
15.2.1 Background _________________ 278
15.2.2 Targets in Breast Cancer _______ 279
15.3 Monoclonal Antibodies and Antibody-Like Structures __ 282
15.3.1 Background _________________ 282
15.3.2 Targets in Breast Cancer _______ 282
15.4 Nucleic Acid Therapies ___ 285
15.4.1 Background _________________ 285
15.4.2 Targets in Breast Cancer _______ 285
15.5 Cell and Gene Therapy ___ 287
15.5.1 Background _________________ 287
15.5.2 Targets in Breast Cancer _______ 288
15.6 Drug Delivery and Nanotechnology _________________ 290
15.6.1 Background _________________ 290
15.6.2 Targets in Breast Cancer _______ 290
16 Breast Cancer Targets by Companies ______________ 292
16.1 Australia ______________ 292
16.2 Austria ________________ 292
16.3 Canada ________________ 293
16.4 China _________________ 294
16.5 Cuba __________________ 294
16.6 Denmark ______________ 294
16.7 Finland ________________ 294
16.8 France ________________ 295
16.9 Germany ______________ 295
16.10 India ________________ 296
16.11 Ireland ______________ 296
16.12 Israel _______________ 297
16.13 Italy ________________ 297
16.14 Japan _______________ 297
16.15 Netherlands __________ 298
16.16 New Zealand _________ 298
16.17 Norway _____________ 298
16.18 South Korea __________ 299
16.19 Sweden _____________ 299
16.20 Switzerland __________ 299
16.21 United Kingdom ______ 300
16.22 USA ________________ 301
16.23 Non-Industrial Bodies __ 307
17 Disclaimer ___________ 308
18 Drug Index ___________ 309
19 Company Index _______ 313
4.1 List of Figures
Figure 1: Distribution of Compound Types among Breast Cancer Drugs ........ 18
Figure 2: Primary Sub-cellular Localization of Drug Targets 19
Figure 3: Visualization of Protein-Protein Interactions Among Antibody Drug
Targets ............. 80
Figure 4: The Drug-Protein Interactome of Breast Cancer Drugs – Main
Cluster..................... 241
Figure 5: The Drug-Protein Interactome of Breast Cancer Drugs – Smaller Clusters
............... 242
Figure 6: Head-to-Head Targeting Interactome of Breast Cancer Drugs ...... 243
4.2 List of Tables
Table 1: Compound Type Versus Primary and Alternate Localization of Drug Target
............... 19
Table 3: Drug Targets of Breast Cancer Drugs Present in the Catalogue of Somatic
Mutations in Cancer and in
the Cancer Gene Census 26
Table 4: Available Protein Expression Profiles of Breast Cancer Drug Targets
.......................... 31
Table 5: Pathway Summary ..................... 34
Table 6: Drug Targets without any Identified Assigned Pathways
.................. 34
Table 7: Pathway Profile According to BioCarta of Breast Cancer Drug Targets
....................... 35
Table 8: Pathway Profile According to KEGG of Breast Cancer Drug Targets . 54
Table 9: Breast Cancer Drugs Targeting Major Singaling Pathways ...............
72
Table 10: Protein-Protein Interactions among Breast Cancer Drug Targets ... 77
Table 11: Number of Available Biological Structures of Breast Cancer Drug
Targets ................ 81
Table 12: Overview of Drug Target Profile Themes .............. 84
Table 13: Drug-Protein Interactome Clusters ..................... 239
Table 14: Fall Out in Terms of the Total Number of Drug Target Mixes, Drugs, and
the Presence of New Drug
Target Mixes by Developmental Stage.... 244
Table 15: Top 5 Pursued Breast Cancer Targets ................. 245
Table 16: Target Profiles of Breast Cancer Drugs in Pre-Registration or on the
Market .......... 247
Table 17: New and Unique Breast Cancer Targets in Phase III Clinical Development
.............. 248
Table 18: New and Unique Breast Cancer Targets in Phase II Clinical Development
............... 250
Table 19 New and Unique Breast Cancer Targets in Phase I Clinical Development
................. 253
Table 20: New and Unique Breast Cancer Targets in Preclinical Development
....................... 255
Table 21: The Progression, Maturity and Competitive Comparison of Breast Cancer
Drug Targets in Development
......... 257
Table 22: Number of Breast Cancer Drug Target Mixes Reported by Line of Therapy
............. 268
Table 23: Number of Head-to-head Competing Small Molecule Drugs for the
Treatment of Breast Cancer by
Drug Target ................. 270
Table 24: Drug Targets of Small Molecule Drugs in Breast Cancer ...............
271
Table 25: Mechanistic Relationship between Small Molecule Drugs in Breast Cancer
............ 276
Table 26: Drug Targets of Peptide Based Drugs in Breast Cancer .................
279
Table 27: Drug Targets of Protein Based Drugs in Breast Cancer .................
280
Table 28: Drug Targets of Monoclonal Antibodies and Antibody-Like Drugs in
Breast Cancer 283
Table 29: Drug Targets of Nucleic Acid Therapies in Breast Cancer ..............
286
Table 30: Potential Forms of Cell Therapy .......................... 287
Table 31: Vectors in Gene Therapy .......... 288
Table 32: Drug Targets of Cell Therapies in Breast Cancer 288
Table 33: Drug Targets of Gene Therapies in Breast Cancer
......................... 289
Table 34: Drug Targets with New Drug Delivery Strategies in Breast Cancer
.......................... 290
Table 35: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in Australia 292
Table 36: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in Austria ... 292
Table 37: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in Canada... 293
Table 38: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in China ...... 294
Table 39: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in Cuba ....... 294
Table 40: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in Denmark 294
Table 41: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in Finland ... 295
Table 42: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in France .... 295
Table 43: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in Germany 295
Table 44: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in India ....... 296
Table 45: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in Ireland.... 296
Table 46: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in Israel ...... 297
Table 47: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in Italy ........ 297
Table 48: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in Japan ..... 297
Table 49: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in the
Netherlands ................. 298
Table 50: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in New Zealand
......... 298
Table 51: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in Norway .. 298
Table 52: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in South Korea
......... 299
Table 53: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in Sweden .. 299
Table 54: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in Switzerland
......... 299
Table 55: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in United
Kingdom ...................... 300
Table 56: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Companies in USA ........ 301
Table 57: Breast Cancer Drugs with Drug Target Mix and Developmental Projects by
Non-Industrial Bodies ... 307