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.
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