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Jingle Xi,
Xuejun Zhu,
Yongmei Feng,
Na Huang,
Guifen Luo,
Yongjun Mao,
Xiaofeng Han, Wang Tian,
Guirong Wang,
Xiaobing Han,
Rongcheng Luo,
Ziwei Huang,
Jing An
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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; · 4.29 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: 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. · 4.80 Impact Factor
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Wang Tian,
Xiaofeng Han,
Maocai Yan,
Yan Xu,
Srinivas Duggineni,
Nan Lin,
Guifen Luo,
Yan Michael Li,
Xiaobing Han,
Ziwei Huang,
Jing An
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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. · 3.42 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. · 2.05 Impact Factor
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Wang Tian,
Xiaofeng Han,
Maocai Yan,
Yan Xu,
SRINIVAS DUGGINENI,
Nan Lin,
Guifen Luo,
Yan Michael Li,
Xiaobing Han,
Ziwei Huang,
Jing An
[show abstract]
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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; · 3.42 Impact Factor
