Wang Tian

State University of New York, New York City, New York, United States

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Publications (9)30.02 Total impact

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    ABSTRACT: The EphA4 receptor tyrosine kinase regulates a variety of physiological and pathological processes during neural development and the formation of tumor blood vessels; thus, it represents a new and promising therapeutic target. We used a combination of phage peptide display and computer modeling/docking approaches and discovered a novel cyclic nonapeptide, now designated TYY. This peptide selectively inhibits the binding of the ephrinA5 ligand with EphA4 and significantly blocks angiogenesis in a 3D matrigel culture system. Molecular docking reveals that TYY recognizes the same binding pocket on EphA4 that the natural ephrin ligand binds to and that the Tyr3 and Tyr4 side chains of TYY are both critical for the TYY/EphA4 interaction. The discovery of TYY introduces a valuable probe of EphA4 function and a new lead for EphA4-targeted therapeutic development.
    PLoS ONE 11/2013; 8(11):e80183. · 3.53 Impact Factor
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    ABSTRACT: Persisters are a small subpopulation of bacterial cells that are dormant and extremely tolerant to antibiotics. The intrinsic antibiotic tolerance of persisters also facilitates the development of multidrug resistance through acquired mechanisms based on drug resistance genes. In this study, we demonstrate that (Z)-4-bromo-5-(bromomethylene)-3-methylfuran-2(5H)-one (BF8) can reduce persistence during Escherichia coli growth and revert the antibiotic tolerance of its persister cells. The effects of BF8 were more profound when the pH was increased from 6 to 8.5. Although BF8 is a quorum sensing (QS) inhibitor, similar effects were observed for the wild-type E. coli RP437 and its ΔluxS mutant, suggesting that these effects did not occur solely through inhibition of AI-2-mediated QS. In addition to its effects on planktonic persisters, BF8 was also found to disperse RP437 biofilms and to render associated cells more sensitive to ofloxacin. At the doses that are effective against E. coli persister cells, BF8 appeared to be safe to the tested normal mammalian cells in vitro and exhibited no long-term cytotoxicity to normal mouse tissues in vivo. These findings broadened the activities of brominated furanones and shed new light on persister control.
    Applied Microbiology and Biotechnology 09/2013; 97(20). · 3.81 Impact Factor
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    ABSTRACT: We have developed a novel class (2-amino-4-phenyl-4H-chromene-3-carboxylate) of inhibitors of tubulin assembly by modifying HA14-1, which is a Bcl-2 inhibitor discovered by our group. Three of these compounds, mHA1, mHA6, and mHA11, showed in vitro cytotoxicities against tumor cells that were more potent and more stable than authentic HA14-1, with IC50 values in the nM range. In contrast, cytotoxic effects of these mHAs on normal cells were slight. Computational docking, colchicine-tubulin competitive binding, and tubulin polymerization studies demonstrated that these compounds bind at the colchicine binding site on tubulin and inhibit the formation of microtubules. Treatment of HL-60/Bcl-2 leukemia and CRL5908 lung cancer cells with these mHAs led to pronounced microtubule density decreases, G2/M cell cycle arrest, and apoptosis, as determined by immunofluorescence microscopy, flow cytometry, and DNA fragmentation analysis. These results support the continued development of these compounds as potential anticancer agents.
    Molecular Cancer Research 05/2013; · 4.35 Impact Factor
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    ABSTRACT: EphB4 is a member of the large Eph receptor tyrosine kinase family. By interacting with its preferred ligand ephrin-B2, which is also a transmembrane protein, EphB4 plays a role in a variety of physiological and pathological processes ranging from bone remodeling to cancer malignancy. EphB4-ephrin-B2 binding occurs at sites of contact between cells. Ephrin-B2 causes EphB4 clustering and increased kinase activity to generate downstream signals that affect cell behavior. Previous work identified a high-affinity antagonistic peptide that targets EphB4, named TNYL-RAW. This peptide is 15 amino acid long, has a molecular weight of ∼1,700Da and binds to the ephrin-binding pocket of EphB4. Here we report the structure-based design and chemical synthesis of two novel small molecules of ∼600-700Da, which were designed starting from the small and functionally critical C-terminal portion of the TNYL-RAW peptide. These compounds inhibit ephrin-B2 binding to EphB4 at low micromolar concentrations. Additionally, although the ephrin-B2 ligand can interact with multiple other Eph receptors besides EphB4, the two compounds retain the high selectivity of the TNYL-RAW peptide in targeting EphB4. TNYL-RAW peptide displacement experiments using the more potent of the two compounds, compound 5, suggest a competitive mode of inhibition. These EphB4 antagonistic compounds can serve as promising templates for the further development of small molecule drugs targeting EphB4.
    Biochemical pharmacology 12/2012; · 4.25 Impact Factor
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    ABSTRACT: The method uses easily available materials and simple reactions, including the key Friedlaender condensation, to assemble the quinoline ring.
    ChemInform 09/2012; 43(38).
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    ABSTRACT: More than 50 new diaminoquinazoline derivatives have been synthesized and evaluated in a colon carcinoma cell growth inhibition assay using HCT116 and SW480 cells. Twenty compounds with good cell growth inhibitory activities (<4 μM) were tested as inhibitors of the β-catenin/T cell transcription factor 4 (Tcf4) signaling pathway using a HCT116 cell-based luciferase reporter assay. Results from the biological activities as well as the comparative molecular field analysis (CoMFA) of the properties of the molecules yielded a preliminary structure-activity relationship (SAR). Three potent compounds, 74, 78, and 86, showed IC(50) values <1 μM for growth inhibition of HCT116 cells and ∼1 μM for SW480 cells, as well as IC(50) values of 1.5-2.5 μM for HCT116 cells with the luciferase reporter assay.
    Journal of Medicinal Chemistry 02/2012; 55(3):1346-59. · 5.48 Impact Factor
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    ABSTRACT: Overactivation or overexpression of β-catenin in the Wnt (wingless) signaling pathway plays an important role in tumorigenesis. Interaction of β-catenin with T-cell factor (Tcf) DNA binding proteins is a key step in the activation of the proliferative genes in response to upstream signals of this Wnt/β-catenin pathway. Recently, we identified a new small molecule inhibitor, named BC21 (C(32)H(36)Cl(2)Cu(2)N(2)O(2)), which effectively inhibits the binding of β-catenin with Tcf4-derived peptide and suppresses β-catenin/Tcf4 driven reporter gene activity. This inhibitor decreases the viability of β-catenin overexpressing HCT116 colon cancer cells that harbor the β-catenin mutation, and more significantly, it inhibits the clonogenic activity of these cells. Down-regulation of c-Myc and cyclin D1 expression, the two important effectors of the Wnt/β-catenin signaling, is confirmed by treating HCT116 cells with BC21. This compound represents a new and modifiable potential anticancer candidate that targets β-catenin/Tcf-4 interaction.
    Biochemistry 01/2012; 51(2):724-31. · 3.38 Impact Factor
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    ABSTRACT: Aberrant activation of the Wnt/β-catenin signaling pathway is associated with a wide range of human cancers. The interaction of β-catenin with T cell factor (Tcf) is a key step in activation of proliferative genes in this pathway. Interruption of this interaction would be a valuable strategy as a tumor therapy. In this study, we developed a novel fluorescein isothiocyanate (FITC)-labeled Tcf4-derived probe for identification of inhibitors of the β-catenin/Tcf4 interaction using a fluorescence polarization assay. This assay shows high potential for use in high-throughput screening for the discovery of inhibitors of the β-catenin/Tcf4 interaction.
    Journal of Biomolecular Screening 11/2011; 17(4):530-4. · 2.01 Impact Factor
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    ABSTRACT: Over-activation or over-expression of β-catenin in the Wnt (wingless) signaling pathway plays an important role in tumorigenesis. Interaction of β-catenin with T-cell factor (Tcf) DNA binding proteins is a key step in the activation of the proliferative genes in response to upstream signals of this Wnt/β-catenin pathway. Recently, we identified a new small molecule inhibitor, Named BC21 (C32H36Cl2Cu2N2O2), which effectively inhibits the binding of β-catenin with Tcf4 derived peptide and suppresses β-catenin/Tcf4 driven reporter gene activity. This inhibitor decreases the viability of β-catenin over-expressing HCT116 colon cancer cells that harbor the β-catenin mutation and, more significantly, it inhibits the clonogenic activity of these cells. Down regulation of c-Myc and cyclin D1 expression, the two important effectors of the Wnt/β-catenin signaling, is confirmed by treating HCT116 cells with BC21. This compound represents a new and modifiable potential anticancer candidate that targets β-catenin/Tcf-4 interaction.
    Biochemistry 01/2011; · 3.19 Impact Factor

Publication Stats

23 Citations
30.02 Total Impact Points

Institutions

  • 2012–2013
    • State University of New York
      New York City, New York, United States
    • Syracuse University
      Syracuse, New York, United States
  • 2011–2013
    • State University of New York Upstate Medical University
      • Department of Pharmacology
      Syracuse, New York, United States