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WIREs Syst Biol Med
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Systems biology‐embedded target validation: improving efficacy in drug discovery

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The pharmaceutical industry is faced with a range of challenges with the ever‐escalating costs of drug development and a drying out of drug pipelines. By harnessing advances in ‐omics technologies and moving away from the standard, reductionist model of drug discovery, there is significant potential to reduce costs and improve efficacy. Embedding systems biology approaches in drug discovery, which seek to investigate underlying molecular mechanisms of potential drug targets in a network context, will reduce attrition rates by earlier target validation and the introduction of novel targets into the currently stagnant market. Systems biology approaches also have the potential to assist in the design of multidrug treatments and repositioning of existing drugs, while stratifying patients to give a greater personalization of medical treatment. WIREs Syst Biol Med 2014, 6:1–11. doi: 10.1002/wsbm.1253 This article is categorized under: Translational, Genomic, and Systems Medicine > Therapeutic Methods Translational, Genomic, and Systems Medicine > Translational Medicine

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A systems biology concept of drug target validation as a mechanistic, diagnostic, and therapeutic package. This concept comprises that a validated target plays a role in the pathogenic mechanism, is altered in disease, is druggable by chemical or biological entities, and is assayable in biological and clinical samples.
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Using mathematical modeling to study drug targets in a network environment can lead to surprising conclusions. (a) The three‐tiered kinase Raf‐MEK‐ERK module shows features of a negative feedback amplifier, providing robustness to change. Simulations using a mathematical model, which have been experimentally validated, suggest that to reduce downstream ERK activity, one needs to either (b) target outside the negative feedback or (c) target both MEK and Raf.
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