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Browsing by Subject "Drug Screening Assays, Antitumor"
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Item Discovery and characterization of small molecules that target the Ral GTPase(Nature Publishing Group, 2014-11-20) Yan, Chao; Liu, Degang; Li, Liwei; Wempe, Michael F.; Guin, Sunny; Khanna, May; Meier, Jeremy; Hoffman, Brenton; Owens, Charles; Wysoczynski, Christina L.; Nitz, Matthew D.; Knabe, Eric W.; Brautigan, David L.; Paschal, Bryce M.; Schwartz, Martin A.; Jones, David; Ross, David; Meroueh, Samy O.; Theodorescu, Dan; Department of Biochemistry & Molecular Biology, IU School of MedicineThe Ras-like GTPases RalA and B are important drivers of tumor growth and metastasis. Chemicals that block Ral function would be valuable as research tools and for cancer therapeutics. Here, we used protein structure analysis and virtual screening to identify drug-like molecules that bind a site on the GDP-form of Ral. Compounds RBC6, RBC8 and RBC10 inhibited Ral binding to its effector RalBP1, Ral-mediated cell spreading in murine fibroblasts and anchorage-independent growth of human cancer cell lines. Binding of RBC8 derivative BQU57 to RalB was confirmed by isothermal titration calorimetry, surface plasma resonance and 15N-HSQC NMR. RBC8 and BQU57 show selectivity for Ral relative to Ras or Rho and inhibit xenograft tumor growth similar to depletion of Ral by siRNA. Our results show the utility of structure-based discovery for development of therapeutics for Ral-dependent cancers.Item Effects of a checkpoint kinase inhibitor, AZD7762, on tumor suppression and bone remodeling(Spandidos Publications, 2018-09) Wang, Luqi; Wang, Yue; Chen, Andy; Jalali, Aydin; Liu, Shengzhi; Guo, Yunxia; Na, Sungsoo; Nakshatri, Harikrishna; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyChemotherapy for suppressing tumor growth and metastasis tends to induce various effects on other organs. Using AZD7762, an inhibitor of checkpoint kinase (Chk) 1 and 2, the present study examined its effect on mammary tumor cells in addition to bone cells (osteoclasts, osteoblasts and osteocytes), using monolayer cell cultures and three-dimensional (3D) cell spheroids. The results revealed that AZD7762 blocked the proliferation of 4T1.2 mammary tumor cells and suppressed the development of RAW264.7 pre-osteoclast cells by downregulating nuclear factor of activated T cells cytoplasmic 1. AZD7762 also promoted the mineralization of MC3T3 osteoblast-like cells and 3D bio-printed bone constructs of MLO-A5 osteocyte spheroids. While a Chk1 inhibitor, PD407824, suppressed the proliferation of tumor cells and the differentiation of pre-osteoclasts, its effect on gene expression in osteoblasts was markedly different compared with AZD7762. Western blotting indicated that the stimulating effect of AZD7762 on osteoblast development was associated with the inhibition of Chk2 and the downregulation of cellular tumor antigen p53. The results of the present study indicated that in addition to acting as a tumor suppressor, AZD7762 may prevent bone loss by inhibiting osteoclastogenesis and stimulating osteoblast mineralization.