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Multitargeted Therapies

CHI Insight Pharma Reports
June 1, 2011
SKU: CHI6428958

Abstract Table of Contents Related Reports

Suites of drugs have been developed that can be used in combination to treat complex diseases that have multiple causes involving multiple targets. In addition, it has been found that many successful small-molecule drugs are promiscuous, i.e., they are single drugs that address multiple targets. This report covers both these major approaches to development of multitargeted therapies. Discussed are:

The discovery and design of promiscuous drugs
The rational design of novel combination therapies designed to address multiple targets, including the uses of synthetic lethality and pathway biology
The emerging area of network pharmacology
Chemical proteomics methods designed to assess the degree of promiscuity of kinase inhibitors and to develop specifically multitargeted kinase inhibitors
The development of second-generation agents to overcome resistance to therapy

Modern drug discovery is generally based on a reductionist model, in which a molecular target has a causative role in a disease process, and modulating that target should ameliorate or cure the disease. This paradigm has resulted in the successful development of numerous therapeutic agents. However, over the past decade, several major factors have been identified that result in the high rates of clinical attrition seen today. One of the biggest factors is that researchers have been addressing complex diseases that are caused by multiple genetic and environmental factors. Thus the reductionist model may not hold in these cases, and drug therapies that address multiple targets are needed.

Multitargeted Therapies: Promiscuous Drugs and Combination Therapies discusses the emerging discipline of network pharmacology, which combines network biology with chemogenomics. Network pharmacology demonstrates that most approved small-molecule drugs are promiscuous. It can be used to develop computational tools to predict the biological activity of compounds, to find new targets for approved drugs as well as for drugs that failed in clinical trials due to efficacy but not safety, and to design new multitargeted drugs.

Also discussed are multitargeted kinase inhibitors. Most kinase inhibitors are promiscuous, and often the efficacy of a kinase inhibitor against a particular type of cancer depends on its ability to address multiple targets. Moreover, the multitargeted nature of a kinase inhibitor may enable its use in treating more than one type of cancer. However, kinase inhibitors may also exhibit off-target adverse effects. We present chemical proteomics methods designed to assess the degree of promiscuity of kinase inhibitors and to develop specifically multitargeted kinase inhibitors.

Multitargeted Therapies: Promiscuous Drugs and Combination Therapies also focuses on development of novel combination therapies designed to address multiple targets. Discussed is the use of synthetic lethality to design combination therapies for cancer. We describe the use of synthetic lethal screening with RNAi to identify chemosensitizing targets for cancer therapeutics. Also described is an RNAi-based synthetic lethal screening approach to developing therapies for p53-negative cancers (p53 is a key tumor suppressor factor in the majority of human cancers).

Another area of focus covered in this report is the use of pathway biology to design rational combination therapies for cancer. Three case studies are included, which involved studying intracellular signaling pathways and how they are affected in cancers that are resistant to certain drugs. These studies were then used to design patient-specific combination therapies to overcome this resistance.

Executive Summary
CHAPTER 1: Introduction; 1.1. Why Multitargeted Therapies?; 1.2. The Structure of this Report
CHAPTER 2: Network Pharmacology in the Design of Promiscuous Drugs; 2.1. Network Pharmacology Demonstrates That Most Approved Small-Molecule Drugs Are Promiscuous; 2.2. Determining the Number of Drug Targets: Revealing the Extent of Polypharmacy in Approved Drugs; 2.3. Global Mapping of Pharmacological Space; 2.4. Correlating Drug-Target Interactions with Protein-Protein Interactions; 2.5. Predicting New Molecular Targets for Known Drugs; 2.6. Designing Multitargeted Small-Molecule Drugs; 2.7. Case Study: Design of Targeted Polypharmacology Inhibitors to Control Nitric Oxide; 2.8. Conclusions
CHAPTER 3: Multitargeted Protein Kinase Inhibitors; 3.1. Introduction; 3.2. The Case of Imatinib; 3.3. Other Approved Small-Molecule Multitargeted Kinase Inhibitors; 3.4. Multitargeted Kinase Inhibitors and Adverse Effects; 3.5. Assessment of the Full Extent of the Promiscuity of Kinase Inhibitors; 3.6. An Exquisitely Specific Kinase Inhibitor; 3.7. Case Study: Discovery of Dual Inhibitors of Tyrosine and Phosphoinositide Kinases; 3.8. Conclusions
CHAPTER 4: Using Synthetic Lethality to Design Combination Therapies for Cancer; 4.1. Introduction; 4.2. Clinical Proof of Concept of a Single-Drug Synthetic Lethality Therapeutic Strategy for Cancer; 4.3. Use of Synthetic Lethal RNAi Screening to Identify Chemosensitizing Targets for Paclitaxel; 4.4. Synthetic Lethal RNAi Screening to Identify Sensitizing Targets for Gemcitabine Therapy in Pancreatic Cancer; 4.5. Synthetic Lethality Approaches to Developing Therapies for p53-Negative Cancers; 4.6. Conclusions
CHAPTER 5: Using Pathway Biology in Design of Rational Combination Therapies for Cancer; 5.1. Introduction; 5.2. Combination Therapies to Simultaneously Block the B-Raf/MEK Pathway and the PI3K-Akt Pathway in KRAS-Mutant Cancers; 5.3. Designing Combination Therapies to Overcome Acquired Resistance to PLX4032 in Metastatic Melanoma; 5.4. EGFR Kinase Inhibitor Resistance in Lung Cancer; 5.5. The Role of Companion Diagnostics and the Personalized Medicine Approach in Developing and Using Pathway-Based Combination Therapies; 5.6. Conclusions
CHAPTER 6: Zalicus’ Combination High-Throughput Screening Technology; 6.1. Corporate History of Zalicus; 6.2. Zalicus’ “Combination High-Throughput Screening” (cHTS) Technology and Its Application to Discovery of Anti-Inflammatory Combi-nation Products; 6.3. Zalicus’ (cHTS) Technology Applied to Discovery of a Novel Combination Therapy for B-Cell Malignancies; 6.4. Conclusions
CHAPTER 7: Outlook; 7.1. The Rationale for Multitargeted Drugs; 7.2. The Structure of This Report; 7.3. Conclusions of the Report
References
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