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  • Tumor cells exposed to the effect of

    2019-10-22

    Tumor Zerumbone exposed to the effect of these compounds were shown to become chemo and radio-sensitive. Based on that, it was possible to anticipate the selectivity requirement for DNA-PK inhibition and the best route for their development. Accordingly, prompted by the clinical significance and the therapeutic value offered by inhibiting such crucial enzyme, we designed this study to utilize a hybrid of computational techniques such as; homology modeling, docking-based virtual screening and molecular dynamic for capturing DNA-PKcs inhibitory candidates employing an FDA-approved drugs as screening database. Herein, we report the results of in-silico study and the biological investigations carried-out on the top candidates.
    Materials and methods
    Results and discussion
    Conclusion In this study, we described the utilization of computational techniques such as; homology modeling, docking, virtual screening and molecular dynamic simulation for repurposing FDA-approved drugs toward capturing inhibitors for the DNA-PK catalytic activity. Our in-silico efforts nominated Praziquantel and Dutasteride as inhibitory candidates. The two candidates showed average DNA-PK inhibitory activity compared to the positive control NU7026 and they enhanced the anti-proliferative effects of two anticancer drugs on human cancer cell lines. We think that, the two drugs worth further structural modification to enhance their DNA-PK inhibitory activity.
    Conflict of interest
    Acknowledgments The authors acknowledge the technical assistance of Ms Varsha Menon. This work is financially supported by AlJalila foundation, project number AJF201409.
    Introduction DNA damage is well known to trigger the activation of DNA repair, cell-cycle arrest, and transcriptional changes. These nuclear effects of DNA damage have been studied extensively (Ciccia and Elledge, 2010, Lord and Ashworth, 2012, Morandell and Yaffe, 2012). By contrast, little is known regarding the regulation of cytoplasmic organelles, such as the Golgi, in response to DNA damage. Our studies, described here, of the regulation of the Golgi protein GOLPH3 (also known as GMx33, GPP34, and yeast Vps74p; Bell et al., 2001, Schmitz et al., 2008, Snyder et al., 2006, Tu et al., 2008, Wu et al., 2000) identify a direct signaling pathway initiated by DNA damage that leads to dramatic reorganization of the Golgi. We previously demonstrated that GOLPH3 is an effector of PtdIns(4)P that links trans-Golgi membranes to the unconventional myosin MYO18A and to the actin cytoskeleton (Dippold et al., 2009). We found that the PtdIns(4)P/GOLPH3/MYO18A/F-actin pathway applies a tensile force to the Golgi, stretching the Golgi ribbon around the nucleus and promoting vesicle exit from the Golgi (Bishé et al., 2012, Dippold et al., 2009, Ng et al., 2013). Unexpectedly, unbiased screening identified GOLPH3 as an oncogene that is amplified in human cancers (Scott et al., 2009), and GOLPH3 overexpression occurs frequently and has negative prognostic significance in several cancers (Hu et al., 2013, Hua et al., 2012, Kunigou et al., 2011, Li et al., 2012, Li et al., 2011, Wang et al., 2012, Zeng et al., 2012, Zhou et al., 2012).
    Results
    Discussion
    Experimental Procedures
    Acknowledgments
    Introduction We have previously reported a range of 2-morpholino-1,3-benzoxazin-4-one compounds that show moderate to high DNA-PK, PI3K and antiplatelet inhibitory activity [1], [2], [3], [4], [5]. These compounds represent a modified scaffold to the corresponding chromone, quinolone and pyridopyrimidinone bicyclic compounds which have also been widely applied to those targets, some of which have undergone extensive clinical and pre-clinical investigation. Chromone and pyridopyrimidone compounds such as LY294002, the archetypal PI3K family inhibitor and PI3Kβ inhibitors such as AZD8186 and AZD6482, have been investigated as in cancer and thrombosis. DNA-PK inhibitors such as the chromone 1a (NU7441), 1b (KU0060648) and quinolinone 2 (Fig. 1) have considerable therapeutic potential as chemo- and radio-potentiating agents in the therapy of cancer by blocking DNA DSB repair [6], [7], [8], [9], [10].