Dallas, TX -- (SBWIRE) -- 06/23/2011 -- 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.

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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.

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