What's wrong with drug screening today

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature Chemical Biology (Impact Factor: 13). 05/2007; 3(4):187-91. DOI: 10.1038/nchembio0407-187
Source: PubMed


Drug screening in the immediate term will be best accomplished by early use of primary cells in which the target of the screen is a network of proteins measured in populations of single cells.

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    • "The primary screening process There is a major gap between medical therapy and drug development , and thus new drugs are being approved at a decreasing rate [1]. The cycle from idea to marketed medicine takes usually 12–15 years and the costs are astronomical [2] [3]. "
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    ABSTRACT: The increased number of therapeutic targets has led to a growing need for screening methods enabling possible inhibitor compound selection. Information for new therapeutic targets has been found mostly from sequencing of the human genome but this knowledge cannot be directly converted into clinically relevant drug molecules. After target identification, the multistep drug development process takes many years and hundreds of millions of dollars are spent without certainty of the outcome. The first and the most critical step in the drug development process is hit selection. The optimal high throughput screening method should provide the highest possible number of true positive hits for further studies and lead discovery. The result should be achieved with low material consumption in a rapid and automated process. Radioactive label based methods are sensitive, but due to the problems arising from the radioactivity, luminescence-based methods have become increasingly popular in screening. In this review, the time-resolved luminescence based quenching resonance energy transfer (QRET) technique is discussed for primary screening. Copyright © 2015 Elsevier B.V. All rights reserved.
    New Biotechnology 02/2015; 32(6). DOI:10.1016/j.nbt.2015.02.007 · 2.90 Impact Factor
    • "Molecular differences between primary and transformed cells of the same tumor type have been well established at both the genomic and proteomic levels. These variations may impact upon the clinical relevance of drug targets and inhibitor efficacy [5] [6] [7] and has challenged the utility and translational relevance of established cancer cell lines used in drug discovery [8] [9] [10]. Thus, primary cell cultures are being increasingly used as platforms to identify oncogenic signaling pathways that faithfully resemble those pathways in patient's tumors and metastases, and therefore may be more relevant for anticancer drug discovery [11]. "
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    ABSTRACT: Mass spectrometry-based technologies are increasingly utilized in drug discovery. Phosphoproteomics in particular has allowed for the efficient surveying of phosphotyrosine signaling pathways involved in various diseases states, most prominently in cancer. We describe a phosphotyrosine-based proteomics screening approach to identify signaling pathways and tyrosine kinase inhibitor targets in highly tumorigenic human lymphoma-like primary cells. We identified several receptor tyrosine kinase pathways and validated SRC family kinases (SFKs) as potential drug targets for targeted selection of small molecule inhibitors. BMS-354825 (dasatinib) and SKI-606 (bosutinib), second and third generation clinical SFK/ABL inhibitors, were found to be potent cytotoxic agents against tumorigenic cells with low toxicity to normal pediatric stem cells. Both SFK inhibitors reduced ERK1/2 and AKT phosphorylation and induced apoptosis. This study supports the adaptation of high-end mass spectrometry techniques for the efficient identification of candidate tyrosine kinases as novel therapeutic targets in primary cancer cell lines.
    Current Drug Discovery Technologies 05/2013; 10(4). DOI:10.2174/15701638113109990001
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    • "failure of a specific pathway to activate, hyper/hyposensitivity of the pathway to physiological modulators, altered kinetics of response, and rewiring of canonical pathways). The technology is based on the assumption that a significant amount of information about a signaling network can be gained by tracking signaling activity as it occurs under different conditions [14]. Generally, this is achieved experimentally by exposing live cells to external modulators, quantifying the state of each signaling node and then comparing it to the basal state. "
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    ABSTRACT: Autoimmune diseases are complex and heterogeneous in nature and show varying responses to therapeutic treatment. A more accurate biological characterization of individual patients would assist in disease classification, prognosis, and treatment decisions. This characterization ideally would incorporate cellular, biochemical, and molecular information that contribute to the inflammatory state. The advent of single-cell network profiling (SCNP) using phospho-flow multiparametric flow cytometry allows insight into the complexity of signaling networks in various cell types. Here, we describe the potential of SCNP to inform on the biological characterization of autoimmune disease, the application in clinical medicine, and the utility in drug development.
    Autoimmunity 11/2010; 43(7):550-9. DOI:10.3109/08916931003674774 · 2.71 Impact Factor
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