br Conclusion The role of
Conclusion The role of DNA-PK target in DNA DSB repair renders this gli1 kinase of great medicinal interest in cancer chemotherapy especially the cancer types of linked to DNA defects. Due to the absence of 3D DNA-PK target structure, different ligand-based methods were applied for design of potent DNA-PK inhibitors. Herein, novel 43 DNA-PK inhibitors database was built and introduced for virtual screening protocols. Based upon the previous SAR analysis, a pharmacophore model was developed and used to screen many proposed chemical compounds as a tool for selection and prediction of hits with high probability to be potentially actives. The pharmacophore model could reflect the essential points responsible for protein interactions. In addition, these results were confirmed by subjecting of these potential hits to 2D QSAR model to measure inhibitory activity. The top selected compounds based upon the morpholino-benzoxazine scaffold were synthesized and their structures were confirmed by different spectroscopic methods. The inhibitory effect of these structures against DNA-PK enzyme was measured and showed high to moderate activity, (IC50 0.25–35µM). Two most active compounds of sulphonamide (7c) with IC50 0.25µM and one of p-OH benzylamine (9f) with IC50 2.5µM derivatives were discovered as micromolar potent structures than reference one. In addition, the cytotoxic effect of these novel compounds was assayed against two cell lines and showed that most of them have anticancer activity with IC50 1.7–50µg/mL range. Docking of some of the found active compounds into the binding pocket of reported DNA-PK homology model and SAR analyses of the poses were done and the data are in agreement with observed inhibitory activity. As a perspective, the novel active compounds could be subjected for in vivo testing on rat with cancer based models for study of their synergetic effect to chemosensitivity and radiosensitivity of the marketed anticancer drugs.
Acknowledgments The authors would like to express their appreciation to the Deanship of Scientific Research at Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia (project # 3067/1434).
Acknowledgments We apologize to all colleagues whose important findings could not be cited owing to space limitations. We are grateful to Tom Blundell for permission to reproduce the crystal structure of DNA-PKcs. We thank Gabriel Balmus, Kate Dry, Josep Forment, Donna Lowe, Wojciech Niedzwiedz, Christine Schmidt, and Paul Wijnhoven for critical reading of the manuscript. A.N.B. is supported by a Cancer Research UK (CRUK) Career Development Fellowship (C29215/A20772). Research in the S.P.J. laboratory is funded by CRUK program grant C6/A18796 and a Wellcome Trust Investigator Award (206388/Z/17/Z), with core institute support from CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S.P.J. receives his salary from the University of Cambridge, UK, supplemented by CRUK (C4750/A21839).
Introduction The Epstein–Barr virus (EBV) is an oncogenic virus implicated in the pathogenesis of a number of human malignancies of both lymphoid and epithelial origins and is associated with nearly 200,000 new malignancies each year worldwide , , . Latent membrane protein 1 (LMP1) is a primary oncoprotein encoded by EBV that plays a key role in both the initiation and progression of nasopharyngeal carcinoma (NPC) . Using newly developed support vector machine (SVM)-based methods, LMP1 was identified as a prognostic biomarker for NPC . LMP1 activates several important oncogenic signaling pathways such as NF-κB, JNK, PI3-K/Akt, MAPK and JAK/STAT and causes various downstream pathological changes in cell proliferation, apoptosis and metastasis . Recently, we found that suppression of LMP1 expression by the LMP1-targeted DNAzyme, DZ1, enhanced radiosensitivity both in vivo and in vitro, which suggested an important role for LMP1 in the regulation of the radiosensitivity of NPC cells.