Lina Wang's scientific contributionswhile working at Indiana University-Purdue University Indianapolis (Indianapolis, United States) and other institutions

Publications (8)

Publications citing this author (234)

    • regulator factor c-Myc and the anti-apoptotic protein Bcl-2 are activated by both NF-κB and STAT3.[15,16]Our research group has previously identified a number of different natural product-like compounds or metal complexes as inhibitors of STAT3 and NF-κB.[17][18][19][20]Benzofuran and its derivatives have received attention due to their presence in natural products and biologically-active molecules.[21][22][23]Benzofuran molecules have been developed as inhibitors of PI3 kinase,[24]mTOR,[25]mPTPB[26]and β-amyloid aggregation.[27]In this study, we sought to conjugate benzofuran motif with Group 9 organometallic compounds, which have garnered increased interest in therapeutic and bioanalytical applications due to their flexible reactivity, water solubility, stability, and relative synthetic ease.[28,29]As
    [Show abstract] [Hide abstract] ABSTRACT: Four benzofuran-conjugated iridium(III) or rhodium (III)-based metal complexes are synthesized to screen as an inhibitor of STAT3 activity in prostate cancer cells. All complexes show the high stability and solubility in the biological system. In this study, an iridium(III) complex engages STAT3 and NF-κB to inhibit their translocation and transcriptional activities. Moreover, complex 1 shows more potential antiproliferative activity against DU145 cells and suppresses tumor growth in a prostate cancer xenograft mouse without observable adverse effects. Complex 1 may provide the basis for developing new therapeutic strategy in vivo and in vitro for the treatment of advanced prostate cancer.
    Full-text · Article · Mar 2017
    • However, as for the cells that have developed into cancer or in the mitotic phase, the SFK protein is placed in open conformation due to the Y527 phosphorylation decomposition and Y416 selfphosphorylation . Thus, they can be activated (Yu et al., 2011; Bai et al., 2012). Once it is activated, Src tyrosine kinase can participated in multiple-functional activities in vivo, including proliferation, differentiation, cell movement, migration, and angiogenesis.
    [Show abstract] [Hide abstract] ABSTRACT: This study aims at observing the expression of activated Src tyrosine kinase in esophageal squamous cell carcinoma (ESCC), and exploring the relationship of Src tyrosine kinase with the occurrence and progression of ESCC. Immunohistochemistry, immunofluorescence, and immunoblotting are employed to investigate the expression of Src tyrosine kinase in the ESCC tissue. Cellular immunofluorescence is used to measure the expression of activated Src tyrosine kinase in TE1 and TE9 cell lines of human ESCC tissues and EPC1-htert and EPC2-htert cell lines of esophageal epithelial cells. Src tyrosine kinase is overexpressed in ESCC tissue and underexpressed in normal esophageal mucosa. Furthermore, it is overexpressed in the TE1 and TE9 cell lines of human ESCC tissue and underexpressed in the EPC1-htert and EPC2-htert cell lines of esophageal epithelial cells. Src tyrosine kinase shows a higher expression in human ESCC tissue than in normal esophageal mucosa. The difference is statistically significant (P < 0.05). The activation of Src tyrosine kinase plays an important role in the occurrence and development of ESCC.
    Article · Aug 2016
    • TMC is believed to specifically block tyrosine phosphorylation of intracellular signal mediators downstream of Src tyrosine kinases in a T cell-specific manner via selective inhibition of protein phosphatase 1 (PP1) and PP2A [18, 20, 21] . However, the Src homol- ogy-2 domain containing protein tyrosine phosphatase-2 (SHP2) was also recently shown to be a putative target for the immunosuppressive activity of TMC [22]. Moreover, Page 7 of 11 Nah et al.
    [Show abstract] [Hide abstract] ABSTRACT: Background: Direct cloning combined with heterologous expression of a secondary metabolite biosynthetic gene cluster has become a useful strategy for production improvement and pathway modification of potentially valuable natural products present at minute quantities in original isolates of actinomycetes. However, precise cloning and efficient overexpression of an entire biosynthetic gene cluster remains challenging due to the ineffectiveness of current genetic systems in manipulating large-sized gene clusters for heterologous as well as homologous expression. Results: A versatile Escherichia coli-Streptomyces shuttle bacterial artificial chromosomal (BAC) conjugation vector, pSBAC, was used along with a cluster tandem integration approach to carry out homologous and heterologous overexpression of a large 80-kb polyketide biosynthetic pathway gene cluster of tautomycetin (TMC), which is a protein phosphatase PP1/PP2A inhibitor and T cell-specific immunosuppressant. Unique XbaI restriction sites were precisely inserted at both border regions of the TMC biosynthetic gene cluster within the chromosome of TMC-producing Streptomyces sp. CK4412, followed by site-specific recombination of pSBAC into the flanking region of the TMC gene cluster. The entire TMC gene cluster was then rescued as a single giant recombinant pSBAC by XbaI digestion of the chromosomal DNA as well as subsequent self-ligation. Next, the recombinant pSBAC construct containing the entire TMC cluster in E. coli was directly conjugated into model Streptomyces strains, resulting in rapid and enhanced TMC production. Moreover, introduction of the TMC cluster-containing pSBAC into wild-type Streptomyces sp. CK4412 as well as a recombinant S. coelicolor strain resulted in a chromosomal tandem repeat of the entire TMC cluster with 14-fold and 5.4-fold enhanced TMC productivities, respectively. Conclusions: The 80-kb TMC biosynthetic gene cluster was isolated in a single integration vector, pSBAC. Introduction of TMC biosynthetic gene cluster in TMC non-producing strains has resulted in similar amount of TMC production yield. Moreover, over-expression of TMC biosynthetic gene cluster in original producing strain and recombinant S. coelicolor dramatically increased TMC production. Thus, this strategy can be employed to develop a custom overexpression scheme of entire metabolite pathway clusters present in actinomycetes.
    Full-text · Article · Sep 2015
    • The preparation and refinement protocols for the protein receptor and all compound structures were performed on the Prepare Protein Wizard and Prepare Ligands modules embedded in the Discovery Studio v3.5. PTP-MEG2 (PDB ID: 4GE6)[20]was prepared by removing water, adding the hydrogen atoms, deleting alternate conformations, standardizing atom names and the ligands were prepared by the procedures of removing duplicates, enumerating isomers, tautomers, and ionization states[42]at a given pH range and generating 3D conformations. Define and Edit binding site tool embedded in Discovery Studio v3.5 was applied to calculate a binding site from a selected ligand.
    [Show abstract] [Hide abstract] ABSTRACT: PTP-MEG2 plays a critical role in the diverse cell signalling processes, so targeting PTP-MEG2 is a promising strategy for various human diseases treatments. In this study, a series of novel dibenzofuran derivatives was synthesized and assayed for their PTP-MEG2 inhibitory activities. 10a with highest inhibitory activity (320 nM) exhibited significant selectivity for PTP-MEG2 over its close homolog SHP2, CDC25 (IC50 > 50 μM). By means of the powerful ''HipHop'' technique, a 3D-QSAR study was carried out to explore structure activity relationship of these molecules. The generated pharmacophore model revealed that the one RA, three Hyd, and two HBA features play an important role in binding to the active site of the target protein-PTP-MEG2. Docking simulation study indicated that 10a achieved its potency and specificity for PTP-MEG2 by targeting unique nearby peripheral binding pockets and the active site. The absorption, distribution, metabolism and excretion (ADME) predictions showed that the 11 compounds hold high potential to be novel lead compounds for targeting PTP-MEG2. Our findings here can provide a new strategy or useful insights for designing the effective PTP-MEG2 inhibitors.
    Article · Mar 2017
    • Previous studies have identified both phosphataseindependent and phosphatase-dependent roles for SHP2 in regulating cell growth and survival [35, 36]. To address this, we investigated the effects of a SHP2 phosphatase inhibitor (II-B08), which has shown anti-proliferative effects in several cancer models [30, 31, 33].
    [Show abstract] [Hide abstract] ABSTRACT: Acquired mutations in KIT are driver mutations in systemic mastocytosis (SM). Here, we tested the role of SHP2/PTPN11 phosphatase in oncogenic KIT signaling using an aggressive SM mouse model. Stable knock-down (KD) of SHP2 led to impaired growth, colony formation, and increased rates of apoptosis in P815 cells. This correlated with defects in signaling to ERK/Bim, Btk, Lyn, and Stat5 pathways in P815-KD cells compared to non-targeting (NT). Retro-orbital injections of P815 NT cells in syngeneic DBA/2 mice resulted in rapid development of aggressive SM within 13-16 days characterized by splenomegaly, extramedullary hematopoiesis, and multifocal liver tumors. In contrast, mice injected with P815 SHP2 KD cells showed less disease burden, including normal spleen weight and cellularity, and significant reductions in mastocytoma cells in spleen, bone marrow, peripheral blood and liver compared to NT controls. Treatment of human mast cell leukemia HMC-1 cells or P815 cells with SHP2 inhibitor II-B08, resulted in reduced colony formation and cell viability. Combining II-B08 with multi-kinase inhibitor Dasatinib showed enhanced efficacy than either inhibitor alone in blocking cell growth pathways and cell viability. Taken together, these results identify SHP2 as a key effector of oncogenic KIT and a therapeutic target in aggressive SM.
    Full-text · Article · Jul 2014
    • As shown in Supplementary Figure S2B, the EC 50 value of 11a-1 on NIH 3T3 cell viability (49.8 ± 5.2 μM) is more than 10 fold higher than that on MeWo cells, indicating that 11a-1 shows less toxicity to normal cells. To further consolidate the target engagement of SHP2, we evaluated two additional SHP2 inhibitors, one is a structurally-related active site-directed SHP2 inhibitor IIB08 (IC 50 = 5.5 μM) [42] , and the other is a structurallyunrelated SHP2 inhibitor SHP099 (IC 50 = 0.07 μM) with a different mode of action, namely allosteric inhibition, reported most recently by Novartis [43]. As shown in Supplementary Figure S2Cand S2D, IIB08 and SHP099 dose-dependently inhibit MeWo cell viability and SHP2 mediated ERK1/2 activation.
    [Show abstract] [Hide abstract] ABSTRACT: Melanoma ranks among the most aggressive and deadly human cancers. Although a number of targeted therapies are available, they are effective only in a subset of patients and the emergence of drug resistance often reduces durable responses. Thus there is an urgent need to identify new therapeutic targets and develop more potent pharmacological agents for melanoma treatment. Herein we report that SHP2 levels are frequently elevated in melanoma, and high SHP2 expression is significantly associated with more metastatic phenotype and poorer prognosis. We show that SHP2 promotes melanoma cell viability, motility, and anchorage-independent growth, through activation of both ERK1/2 and AKT signaling pathways. We demonstrate that SHP2 inhibitor 11a-1 effectively blocks SHP2-mediated ERK1/2 and AKT activation and attenuates melanoma cell viability, migration and colony formation. Most importantly, SHP2 inhibitor 11a-1 suppresses xenografted melanoma tumor growth, as a result of reduced tumor cell proliferation and enhanced tumor cell apoptosis. Taken together, our data reveal SHP2 as a novel target for melanoma and suggest SHP2 inhibitors as potential novel therapeutic agents for melanoma treatment.
    Full-text · Article · Sep 2016
    • X-ray structure of 7-SHP-2 further implies that the distal biphenyl group of 7 makes additional hydrophobic contacts with a region of SHP-2 highly divergent among the PTPs, thereby enhancing its potency and specificity. A unique ‘double click’ strategy was recently proposed by Zhang, which aims at coupling two functional groups with a core pTyr mimetic for further increasing interactions with the subpockets of PTPs [45]. Consequently, various azides were ‘clicked’ onto five different dipropargyl salicylic acid scaffolds in generating a 212-member library, from which tridentate compound 8 (IC50 = 160 nM) was disclosed as a new potent MptpB inhibitor.
    [Show abstract] [Hide abstract] ABSTRACT: Protein tyrosine phosphatases (PTPs) are crucial regulators for numerous biological processes in nature. The dysfunction and overexpression of many PTP members have been demonstrated to cause fatal human diseases such as cancers, diabetes, obesity, neurodegenerative diseases and autoimmune disorders. In the past decade, considerable efforts have been devoted to the production of PTPs inhibitors by both academia and the pharmaceutical industry. However, there are only limited drug candidates in clinical trials and no commercial drugs have been approved, implying that further efficient discovery of novel chemical entities competent for inhibition of the specific PTP target in vivo remains yet a challenge. In light of the click-chemistry paradigm which advocates the utilization of concise and selective carbon-heteroatom ligation reactions for the modular construction of useful compound libraries, the Cu(I)-catalyzed azidealkyne 1,3-dipolar cycloaddition reaction (CuAAC) has fueled enormous energy into the modern drug discovery. Recently, this ingenious chemical ligation tool has also revealed efficacious and expeditious in establishing large combinatorial libraries for the acquisition of novel PTPs inhibitors with promising pharmacological profiles. We thus offer here a comprehensive review highlighting the development of PTPs inhibitors accelerated by the CuAAC click chemistry.
    Full-text · Article · Mar 2012
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