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      DrugTargetSeqR: a genomics- and CRISPR/Cas9-based method to analyze drug targets

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      Nature chemical biology

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          Abstract

          To identify the physiological targets of drugs and bioactive small molecules we have developed an approach, named DrugTargetSeqR, which combines high-throughput sequencing, computational mutation discovery and CRISPR/Cas9-based genome editing. We apply this approach to ispinesib and YM155, drugs that have undergone clinical trials as anti-cancer agents, and demonstrate target identification and uncover genetic and epigenetic mechanisms likely to cause drug resistance in human cancer cells.

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          Most cited references19

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          Target identification and mechanism of action in chemical biology and drug discovery.

          Target-identification and mechanism-of-action studies have important roles in small-molecule probe and drug discovery. Biological and technological advances have resulted in the increasing use of cell-based assays to discover new biologically active small molecules. Such studies allow small-molecule action to be tested in a more disease-relevant setting at the outset, but they require follow-up studies to determine the precise protein target or targets responsible for the observed phenotype. Target identification can be approached by direct biochemical methods, genetic interactions or computational inference. In many cases, however, combinations of approaches may be required to fully characterize on-target and off-target effects and to understand mechanisms of small-molecule action.
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            Next-generation DNA sequencing.

            DNA sequence represents a single format onto which a broad range of biological phenomena can be projected for high-throughput data collection. Over the past three years, massively parallel DNA sequencing platforms have become widely available, reducing the cost of DNA sequencing by over two orders of magnitude, and democratizing the field by putting the sequencing capacity of a major genome center in the hands of individual investigators. These new technologies are rapidly evolving, and near-term challenges include the development of robust protocols for generating sequencing libraries, building effective new approaches to data-analysis, and often a rethinking of experimental design. Next-generation DNA sequencing has the potential to dramatically accelerate biological and biomedical research, by enabling the comprehensive analysis of genomes, transcriptomes and interactomes to become inexpensive, routine and widespread, rather than requiring significant production-scale efforts.
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              Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen.

              Small molecules that perturb specific protein functions are valuable tools for dissecting complex processes in mammalian cells. A combination of two phenotype-based screens, one based on a specific posttranslational modification, the other visualizing microtubules and chromatin, was used to identify compounds that affect mitosis. One compound, here named monastrol, arrested mammalian cells in mitosis with monopolar spindles. In vitro, monastrol specifically inhibited the motility of the mitotic kinesin Eg5, a motor protein required for spindle bipolarity. All previously known small molecules that specifically affect the mitotic machinery target tubulin. Monastrol will therefore be a particularly useful tool for studying mitotic mechanisms.
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                Author and article information

                Journal
                101231976
                32624
                Nat Chem Biol
                Nat. Chem. Biol.
                Nature chemical biology
                1552-4450
                1552-4469
                30 May 2014
                15 June 2014
                August 2014
                01 February 2015
                : 10
                : 8
                : 626-628
                Author notes
                Correspondence: Kapoor@ 123456rockefeller.edu , The Rockefeller University, 1230 York Avenue, New York, NY10065, (212) 327 -8176
                Article
                NIHMS593232
                10.1038/nchembio.1551
                4123312
                24929528
                a068facd-9a5e-4105-bbef-63a6d45db5a7
                History
                Categories
                Article

                Biochemistry
                Biochemistry

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