ReportsnReports – Multitargeted Therapies: Promiscuous Drugs and Combination Therapies

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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 …

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).

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  • 1. Multitargeted Therapies: Promiscuous Drugs and Combination TherapiesSuites of drugs have been developed that can be used in combination to treat complexdiseases that have multiple causes involving multiple targets. In addition, it has been foundthat many successful small-molecule drugs are promiscuous, i.e., they are single drugs thataddress multiple targets. This report covers both these major approaches to development ofmultitargeted 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 therapyModern drug discovery is generally based on a reductionist model, in which a moleculartarget has a causative role in a disease process, and modulating that target shouldameliorate or cure the disease. This paradigm has resulted in the successful development ofnumerous therapeutic agents. However, over the past decade, several major factors havebeen identified that result in the high rates of clinical attrition seen today. One of thebiggest factors is that researchers have been addressing complex diseases that are causedby multiple genetic and environmental factors. Thus the reductionist model may not hold inthese cases, and drug therapies that address multiple targets are needed.Multitargeted Therapies: Promiscuous Drugs and Combination Therapies discusses theemerging discipline of network pharmacology, which combines network biology withchemogenomics. Network pharmacology demonstrates that most approved small-moleculedrugs are promiscuous. It can be used to develop computational tools to predict thebiological activity of compounds, to find new targets for approved drugs as well as for drugsthat failed in clinical trials due to efficacy but not safety, and to design new multitargeteddrugs.Buy Now: Multitargeted Therapies MarketBrowse All: Newly Published Market Research ReportsAlso 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 itsability to address multiple targets. Moreover, the multitargeted nature of a kinase inhibitormay enable its use in treating more than one type of cancer. However, kinase inhibitorsmay also exhibit off-target adverse effects. We present chemical proteomics methodsdesigned to assess the degree of promiscuity of kinase inhibitors and to develop specificallymultitargeted kinase inhibitors.
  • 2. Multitargeted Therapies: Promiscuous Drugs and Combination Therapies also focuses ondevelopment of novel combination therapies designed to address multiple targets.Discussed is the use of synthetic lethality to design combination therapies for cancer. Wedescribe the use of synthetic lethal screening with RNAi to identify chemosensitizing targetsfor cancer therapeutics. Also described is an RNAi-based synthetic lethal screening approachto developing therapies for p53-negative cancers (p53 is a key tumor suppressor factor inthe majority of human cancers).Another area of focus covered in this report is the use of pathway biology to design rationalcombination therapies for cancer. Three case studies are included, which involved studyingintracellular signaling pathways and how they are affected in cancers that are resistant tocertain drugs. These studies were then used to design patient-specific combinationtherapies to overcome this resistance.Table Of ContentsExecutive Summary vCHAPTER 1Introduction 11.1. Why Multitargeted Therapies? 1Treating Complex Diseases with Combinations of Currently Marketed Drugs 2Use and Development of Fixed-Dose Combination Therapeutics 3Many Current Successful Drugs Address More Than One Molecular Target 4Network Biology, Network Pharmacology, and Polypharmacy 41.2. The Structure of this Report 5CHAPTER 2 Network Pharmacology in the Design of Promiscuous Drugs 62.1. Network Pharmacology Demonstrates That Most Approved Small-Molecule Drugs ArePromiscuous 62.2. Determining the Number of Drug Targets: Revealing the Extent of Polypharmacy inApproved Drugs 62.3. Global Mapping of Pharmacological Space 82.4. Correlating Drug-Target Interactions with Protein-Protein Interactions 112.5. Predicting New Molecular Targets for Known Drugs 122.6. Designing Multitargeted Small-Molecule Drugs 142.7. Case Study: Design of Targeted Polypharmacology Inhibitors to Control Nitric Oxide 162.8. Conclusions 18CHAPTER 3 Multitargeted Protein Kinase Inhibitors 203.1. Introduction 20
  • 3. 3.2. The Case of Imatinib 21Developing Means to Deal with Imatinib Resistance 22Developing Means to Deal with Imatinib/Dasatinib/Nilotinib Resistance Due to the T315IMutation 23Multitargeting by Imatinib Makes Possible the Targeting of New Indications 24Approval of Second-Generation Kinases for Treatment of Newly Diagnosed CML 243.3. Other Approved Small-Molecule Multitargeted Kinase Inhibitors 253.4. Multitargeted Kinase Inhibitors and Adverse Effects 283.5. Assessment of the Full Extent of the Promiscuity of Kinase Inhibitors 29Using Chemical Proteomics Technology in High-Throughput Kinase Profiling 313.6. An Exquisitely Specific Kinase Inhibitor 323.7. Case Study: Discovery of Dual Inhibitors of Tyrosine and Phosphoinositide Kinases 333.8. Conclusions 36CHAPTER 4 Using Synthetic Lethality to Design Combination Therapies for Cancer384.1. Introduction 38What Is Synthetic Lethality? 384.2. Clinical Proof of Concept of a Single-Drug Synthetic Lethality Therapeutic Strategy forCancer 394.3. Use of Synthetic Lethal RNAi Screening to Identify Chemosensitizing Targets forPaclitaxel 40In Lung Cancer 40In Breast Cancer 424.4. Synthetic Lethal RNAi Screening to Identify Sensitizing Targets for GemcitabineTherapy in Pancreatic Cancer 434.5. Synthetic Lethality Approaches to Developing Therapies for p53-Negative Cancers 444.6. Conclusions 46CHAPTER 5 Using Pathway Biology in Design of Rational Combination Therapies forCancer 475.1. Introduction 475.2. Combination Therapies to Simultaneously Block the B-Raf/MEK Pathway and the PI3K-Akt Pathway in KRAS-Mutant Cancers 485.3. Designing Combination Therapies to Overcome Acquired Resistance to PLX4032 inMetastatic Melanoma 49Resistance Mediated Via the COT/MAP3K8 Oncogene 50PLX4032 Resistance via Upregulation of PDGFRß or N-RAS 51Combination Targeted Therapy and Immunotherapy with PLX4032 and Ipilimumab 52A Combination Therapy with PLX4032 and an Inhibitor of Aberrant Differentiation Pathways
  • 4. in Melanoma 52Summary of Potential Combination Therapies to Overcome PLX4032 Resistance 535.4. EGFR Kinase Inhibitor Resistance in Lung Cancer 54Two Mechanisms of Resistance to EGFR Kinase Inhibitors in EGFR-Mutant NSCLC 56Acquired Resistance via the T790M Gatekeeper Mutation 56Acquired Resistance via MET Amplification and/or Activation 57Summary of Findings on EGFR Kinase Inhibitor Resistance in Lung Cancer 595.5. The Role of Companion Diagnostics and the Personalized Medicine Approach inDeveloping and Using Pathway-Based Combination Therapies 595.6. Conclusions 60CHAPTER 6 Zalicus’ Combination High-Throughput Screening Technology 616.1. Corporate History of Zalicus 616.2. Zalicus’ “Combination High-Throughput Screening” (cHTS) Technology and ItsApplication to Discovery of Anti-Inflammatory Combi-nation Products 626.3. Zalicus’ (cHTS) Technology Applied to Discovery of a Novel Combination Therapy for B-Cell Malignancies 636.4. Conclusions 65CHAPTER 7 Outlook 667.1. The Rationale for Multitargeted Drugs 66Complex Diseases Have Multiple “Causes” 66Many Approved Drugs (Old and New) Are Multitargeted 67Network Biology Shows the Need for Multitargeted Agents 677.2. The Structure of This Report 67Network Pharmacology in the Design of Promiscuous Drugs 67Multitargeted Kinase Inhibitors 68Development of Combination Therapies to Address Multiple Targets 697.3. Conclusions of the Report 71LIST OF FIGURESFigure 2.1. Simplified Diagram of a Polypharmacology Network for 15 Hypothetical ProteinsFigure 2.2. Distribution of Molecular Properties of Compounds for Human Targets (< 100 nMActivity): Determination of “Druggability”Figure 2.3. Biochemistry of NO Synthesis and Control of NO LevelsFigure 2.4. L-IPO: A Polypharmacological Inhibitor of Both NOS and DDAHFigure 3.1. Chemical Proteomics Technologies for Assessing the Specificity of KinaseInhibitorsFigure 4.1. Synthetic LethalityFigure 5.1. Simplified Diagram of the KRAS/ERK Pathway
  • 5. LIST OF TABLESTable 3.1. Select Approved Small-Molecule Kinase InhibitorsTable 3.2. FDA-Approved Agents for Treatment of Renal Cell CarcinomaTable 5.1. Putative Mechanisms and Potential Combination Therapies for PLX4032Resistance in BRAFV600E-Driven Metastatic MelanomaTable 5.2. Examples of Compounds in Development with the Potential to Overcome T790M-Based Resistance to EGFR Kinase InhibitorsLatest Market Research Reports: The Future of Interior Products in the UK to 2015: Recovery to Gather Pace from 2012 UK Foodservice Operators’ Industry Outlook Survey 2011–2012: Business Sentiments and Spending Priorities 2011 Deep Research Report on Global and China CPV Solar Industry Global and China CPV Solar Industry, (2011 Deep Research Report) European IT Supplier Industry Outlook Survey 2011–2012: Industry Dynamics, Market Trends and Opportunities, Marketing Spend and Sales Strategies 2011 Deep Research Report on Global and China CPV Solar IndustryAbout Us:ReportsnReports is an online library of over 75,000 market research reports and in-depthmarket research studies & analysis of over 5000 micro markets. We provide 24/7 online andoffline support to our customers. Get in touch with us for your needs of market researchreports.Follow us on Twitter: http://twitter.com/marketsreportsOur Facebook Page:http://www.facebook.com/pages/ReportsnReports/191441427571689Contact:Mr.Priyank7557 Rambler road,Suite727,Dallas,TX75231Tel: +1-888-989-8004E-mail: sales@reportsnreports.comhttp://www.reportsnreports.comBlog: http://www.reportsnreportsblog.com/