ReportsnReports - Multitargeted Therapies: Promiscuous Drugs and Combination Therapies

DALLAS, June 23, 2011 -

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‘Multitargeted Therapies: Promiscuous Drugs and
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Multitargeted Therapies: Promiscuous Drugs and Combination
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Report Summary

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 on href="www.reportsnreports.com/reports/89350-multitargeted-therapies-promiscuous-drugs-and-combination-therap.html">
Multitargeted Therapies 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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