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      Drug Design, Development and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the design and development of drugs, as well as the clinical outcomes, patient safety, and programs targeted at the effective and safe use of medicines. Sign up for email alerts here.

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      Drug design with Cdc7 kinase: a potential novel cancer therapy target


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          Identification of novel molecular targets is critical in development of new and efficient cancer therapies. Kinases are one of the most common drug targets with a potential for cancer therapy. Cell cycle progression is regulated by a number of kinases, some of which are being developed to treat cancer. Cdc7 is a serine-threonine kinase originally discovered in budding yeast, which has been shown to be necessary to initiate the S phase. Inhibition of Cdc7 in cancer cells retards the progression of the S phase, accumulates DNA damage, and induces p53-independent cell death, but the same treatment in normal cells does not significantly affect of less than viability. Low-molecular-weight compounds that inhibit Cdc7 kinase with an IC 50 10 nM have been identified, and shown to be effective in the inhibition of tumor growth in animal models. Thus Cdc7 kinase can be recognized as a novel molecular target for cancer therapy.

          Most cited references61

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          The protein kinase family: conserved features and deduced phylogeny of the catalytic domains.

          In recent years, members of the protein kinase family have been discovered at an accelerated pace. Most were first described, not through the traditional biochemical approach of protein purification and enzyme assay, but as putative protein kinase amino acid sequences deduced from the nucleotide sequences of molecularly cloned genes or complementary DNAs. Phylogenetic mapping of the conserved protein kinase catalytic domains can serve as a useful first step in the functional characterization of these newly identified family members.
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            Protein kinase inhibitors: insights into drug design from structure.

            Protein kinases are targets for treatment of a number of diseases. This review focuses on kinase inhibitors that are in the clinic or in clinical trials and for which structural information is available. Structures have informed drug design and have illuminated the mechanism of inhibition. We review progress with the receptor tyrosine kinases (growth factor receptors EGFR, VEGFR, and FGFR) and nonreceptor tyrosine kinases (Bcr-Abl), where advances have been made with cancer therapeutic agents such as Herceptin and Gleevec. Among the serine-threonine kinases, p38, Rho-kinase, cyclin-dependent kinases, and Chk1 have been targeted with productive results for inflammation and cancer. Structures have provided insights into targeting the inactive or active form of the kinase, for targeting the global constellation of residues at the ATP site or less conserved additional pockets or single residues, and into targeting noncatalytic domains.
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              Rad51-deficient vertebrate cells accumulate chromosomal breaks prior to cell death.

              Yeast rad51 mutants are viable, but extremely sensitive to gamma-rays due to defective repair of double-strand breaks. In contrast, disruption of the murine RAD51 homologue is lethal, indicating an essential role of Rad51 in vertebrate cells. We generated clones of the chicken B lymphocyte line DT40 carrying a human RAD51 transgene under the control of a repressible promoter and subsequently disrupted the endogenous RAD51 loci. Upon inhibition of the RAD51 transgene, Rad51- cells accumulated in the G2/M phase of the cell cycle before dying. Chromosome analysis revealed that most metaphase-arrested Rad51- cells carried isochromatid-type breaks. In conclusion, Rad51 fulfils an essential role in the repair of spontaneously occurring chromosome breaks in proliferating cells of higher eukaryotes.

                Author and article information

                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug design, development and therapy
                Dove Medical Press
                6 February 2009
                : 2
                : 255-264
                [1 ] Carna Biosciences, Inc., Kobe, Japan
                [2 ] Genome Dynamics Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
                Author notes
                Correspondence: Hisao Masai, Genome Dynamics Project, Tokyo, Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan, Tel +81 3 5685 2264, Fax +81 3 5685 2964, Email masai-hs@ 123456igakuken.or.jp
                © 2008 Sawa and Masai, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                Pharmacology & Pharmaceutical medicine
                cdc7 kinase,cell cycle,replication fork,genome stability,dna damages,atp-binding pocket,kinase inhibitor


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