Author: Allan Haberman, PhD
Executive Summary v
CHAPTER 1
Introduction 1
1.1. Why Multitargeted Therapies? 1
Treating Complex Diseases with Combinations of Currently Marketed Drugs 2
Use and Development of Fixed-Dose Combination Therapeutics 3
Many Current Successful Drugs Address More Than One Molecular Target 4
Network Biology, Network Pharmacology, and Polypharmacy 4
1.2. The Structure of this Report 5
CHAPTER 2
Network Pharmacology in the Design of Promiscuous Drugs 6
2.1. Network Pharmacology Demonstrates That Most Approved Small-Molecule Drugs Are Promiscuous 6
2.2. Determining the Number of Drug Targets: Revealing the Extent of Polypharmacy in Approved Drugs 6
2.3. Global Mapping of Pharmacological Space 8
2.4. Correlating Drug-Target Interactions with Protein-Protein Interactions 11
2.5. Predicting New Molecular Targets for Known Drugs 12
2.6. Designing Multitargeted Small-Molecule Drugs 14
2.7. Case Study: Design of Targeted Polypharmacology Inhibitors to Control Nitric Oxide 16
2.8. Conclusions 18
CHAPTER 3
Multitargeted Protein Kinase Inhibitors 20
3.1. Introduction 20
3.2. The Case of Imatinib 21
Developing Means to Deal with Imatinib Resistance 22
Developing Means to Deal with Imatinib/Dasatinib/Nilotinib Resistance Due to the T315I Mutation 23
Multitargeting by Imatinib Makes Possible the Targeting of New Indications 24
Approval of Second-Generation Kinases for Treatment of Newly Diagnosed CML 24
3.3. Other Approved Small-Molecule Multitargeted Kinase Inhibitors 25
3.4. Multitargeted Kinase Inhibitors and Adverse Effects 28
3.5. Assessment of the Full Extent of the Promiscuity of Kinase Inhibitors 29
Using Chemical Proteomics Technology in High-Throughput Kinase Profiling 31
3.6. An Exquisitely Specific Kinase Inhibitor 32
3.7. Case Study: Discovery of Dual Inhibitors of Tyrosine and Phosphoinositide Kinases 33
3.8. Conclusions 36
CHAPTER 4
Using Synthetic Lethality to Design Combination Therapies for Cancer 38
4.1. Introduction 38
What Is Synthetic Lethality? 38
4.2. Clinical Proof of Concept of a Single-Drug Synthetic Lethality Therapeutic Strategy for Cancer 39
4.3. Use of Synthetic Lethal RNAi Screening to Identify Chemosensitizing Targets for Paclitaxel 40
In Lung Cancer 40
In Breast Cancer 42
4.4. Synthetic Lethal RNAi Screening to Identify Sensitizing Targets for Gemcitabine Therapy in Pancreatic Cancer 43
4.5. Synthetic Lethality Approaches to Developing Therapies for p53-Negative Cancers 44
4.6. Conclusions 46
CHAPTER 5
Using Pathway Biology in Design of Rational Combination Therapies for Cancer 47
5.1. Introduction 47
5.2. Combination Therapies to Simultaneously Block the B-Raf/MEK Pathway and the PI3K-Akt Pathway in KRAS-Mutant Cancers 48
5.3. Designing Combination Therapies to Overcome Acquired Resistance to PLX4032 in Metastatic Melanoma 49
Resistance Mediated Via the COT/MAP3K8 Oncogene 50
PLX4032 Resistance via Upregulation of PDGFRß or N-RAS 51
Combination Targeted Therapy and Immunotherapy with PLX4032 and Ipilimumab 52
A Combination Therapy with PLX4032 and an Inhibitor of Aberrant Differentiation Pathways in Melanoma 52
Summary of Potential Combination Therapies to Overcome PLX4032 Resistance 53
5.4. EGFR Kinase Inhibitor Resistance in Lung Cancer 54
Two Mechanisms of Resistance to EGFR Kinase Inhibitors in EGFR-Mutant NSCLC 56
Acquired Resistance via the T790M Gatekeeper Mutation 56
Acquired Resistance via MET Amplification and/or Activation 57
Summary of Findings on EGFR Kinase Inhibitor Resistance in Lung Cancer 59
5.5. The Role of Companion Diagnostics and the Personalized Medicine Approach in Developing and Using Pathway-Based Combination Therapies 59
5.6. Conclusions 60
CHAPTER 6
Zalicus’ Combination High-Throughput Screening Technology 61
6.1. Corporate History of Zalicus 61
6.2. Zalicus’ “Combination High-Throughput Screening” (cHTS) Technology and Its Application to Discovery of Anti-Inflammatory Combi-nation Products 62
6.3. Zalicus’ (cHTS) Technology Applied to Discovery of a Novel Combination Therapy for B-Cell Malignancies 63
6.4. Conclusions 65
CHAPTER 7
Outlook 66
7.1. The Rationale for Multitargeted Drugs 66
Complex Diseases Have Multiple “Causes” 66
Many Approved Drugs (Old and New) Are Multitargeted 67
Network Biology Shows the Need for Multitargeted Agents 67
7.2. The Structure of This Report 67
Network Pharmacology in the Design of Promiscuous Drugs 67
Multitargeted Kinase Inhibitors 68
Development of Combination Therapies to Address Multiple Targets 69
7.3. Conclusions of the Report 71
References 72
About Cambridge Healthtech Institute 85