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Featured researches published by Jun Xian.


Journal of Biomolecular Screening | 2010

Identification of Translational Activators of Glial Glutamate Transporter EAAT2 through Cell-Based High-Throughput Screening: An Approach to Prevent Excitotoxicity

Craig K. Colton; Qiongman Kong; Liching Lai; Michael X. Zhu; Kathleen Seyb; Gregory D. Cuny; Jun Xian; Marcie A. Glicksman; Chien Liang Glenn Lin

Excitotoxicity has been implicated as the mechanism of neuronal damage resulting from acute insults such as stroke, epilepsy, and trauma, as well as during the progression of adult-onset neurodegenerative disorders such as Alzheimer’s disease and amyotrophic lateral sclerosis (ALS). Excitotoxicity is defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, leading to neuronal injury or death. One potential approach to protect against excitotoxic neuronal damage is enhanced glutamate reuptake. The glial glutamate transporter EAAT2 is the quantitatively dominant glutamate transporter and plays a major role in clearance of glutamate. Expression of EAAT2 protein is highly regulated at the translational level. In an effort to identify compounds that can induce translation of EAAT2 transcripts, a cell-based enzyme-linked immunosorbent assay was developed using a primary astrocyte line stably transfected with a vector designed to identify modulators of EAAT2 translation. This assay was optimized for high-throughput screening, and a library of approximately 140,000 compounds was tested. In the initial screen, 293 compounds were identified as hits. These 293 hits were retested at 3 concentrations, and a total of 61 compounds showed a dose-dependent increase in EAAT2 protein levels. Selected compounds were tested in full 12-point dose-response experiments in the screening assay to assess potency as well as confirmed by Western blot, immunohistochemistry, and glutamate uptake assays to evaluate the localization and function of the elevated EAAT2 protein. These hits provide excellent starting points for developing therapeutic agents to prevent excitotoxicity.


Bioorganic & Medicinal Chemistry Letters | 2012

Structure-activity relationship study of beta-carboline derivatives as haspin kinase inhibitors

Gregory D. Cuny; Natalia P. Ulyanova; Debasis Patnaik; Ji-Feng Liu; Xiangjie Lin; Ken Auerbach; Soumya S. Ray; Jun Xian; Marcie A. Glicksman; Ross L. Stein; Jonathan M.G. Higgins

Haspin is a serine/threonine kinase that phosphorylates Thr-3 of histone H3 in mitosis that has emerged as a possible cancer therapeutic target. High throughput screening of approximately 140,000 compounds identified the beta-carbolines harmine and harmol as moderately potent haspin kinase inhibitors. Based on information obtained from a structure-activity relationship study previously conducted for an acridine series of haspin inhibitors in conjunction with in silico docking using a recently disclosed crystal structure of the kinase, harmine analogs were designed that resulted in significantly increased haspin kinase inhibitory potency. The harmine derivatives also demonstrated less activity towards DYRK2 compared to the acridine series. In vitro mouse liver microsome stability and kinase profiling of a representative member of the harmine series (42, LDN-211898) are also presented.


Journal of Biomolecular Screening | 2008

Identification of small molecule inhibitors of the mitotic kinase haspin by high-throughput screening using a homogeneous time-resolved fluorescence resonance energy transfer assay.

Debasis Patnaik; Jun Xian; Marcie A. Glicksman; Gregory D. Cuny; Ross L. Stein; Jonathan M.G. Higgins

Haspin/Gsg2 is a kinase that phosphorylates histone H3 at Thr-3 (H3T3ph) during mitosis. Its depletion by RNA interference results in failure of chromosome alignment and a block in mitosis. Haspin, therefore, is a novel target for development of antimitotic agents. We report the development of a high-throughput time-resolved fluorescence resonance energy transfer (TR-FRET) kinase assay for haspin. Histone H3 peptide was used as a substrate, and a europium-labeled H3T3ph phosphospecific monoclonal antibody was used to detect phosphorylation. A library of 137632 small molecules was screened at Km concentrations of ATP and peptide to allow identification of diverse inhibitor types. Reconfirmation of hits and IC 50 determinations were carried out with the TR-FRET assay and by a radiometric assay using recombinant histone H3 as the substrate. A preliminary assessment of specificity was made by testing inhibition of 2 unrelated kinases. EC 50 values in cells were determined using a cell-based ELISA of H3T3ph. Five compounds were selected as leads based on potency and chemical structure considerations. These leads form the basis for the development of specific inhibitors of haspin that will have clear utility in basic research and possible use as starting points for development of antimitotic anticancer therapeutics. (Journal of Biomolecular Screening 2008:1025-1034)


Analytical Biochemistry | 2008

Small Molecule Inhibitors of Phosphatidylcholine Transfer Protein/StarD2 Identified by High Throughput Screening

Neil Wagle; Jun Xian; Ekaterina Y. Shishova; Jie Wei; Marcie A. Glicksman; Gregory D. Cuny; Ross L. Stein; David E. Cohen

Phosphatidylcholine transfer protein (PC-TP, also referred to as StarD2) is a highly specific intracellular lipid-binding protein that catalyzes the transfer of phosphatidylcholines between membranes in vitro. Recent studies have suggested that PC-TP in vivo functions to regulate fatty acid and glucose metabolism, possibly via interactions with selected other proteins. To begin to address the relationship between activity in vitro and biological function, we undertook a high-throughput screen to identify small-molecule inhibitors of the phosphatidylcholine transfer activity of PC-TP. After adapting a fluorescence quench assay to measure phosphatidylcholine transfer activity, we screened 114,752 compounds of a small-molecule library. The high-throughput screen identified 14 potential PC-TP inhibitors. Of these, 6 compounds exhibited characteristics consistent with specific inhibition of PC-TP activity, with IC(50) values that ranged from 4.1 to 95.0muM under conditions of the in vitro assay. These compounds should serve as valuable reagents to elucidate the biological function of PC-TP. Because mice with homozygous disruption of the PC-TP gene (Pctp) are sensitized to insulin action and relatively resistant to the development of atherosclerosis, these inhibitors may also prove to be of value in the management of diabetes and atherosclerotic cardiovascular diseases.


Bioorganic & Medicinal Chemistry Letters | 2010

Structure–activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors

Gregory D. Cuny; Maxime Robin; Natalia P. Ulyanova; Debasis Patnaik; Valérie Pique; Gilles Casano; Ji-Feng Liu; Xiangjie Lin; Jun Xian; Marcie A. Glicksman; Ross L. Stein; Jonathan M.G. Higgins


Archive | 2010

Compositions and Methods for Inhibiting Tumor Growth

Amy Baldwin; Dorre Grueneberg; Ed Harlow; Jun Xian; Karl Münger; Karin Hellner; Marcie A. Glicksman; Ross L. Stein; Gregory D. Cuny


Archive | 2011

Beta-Carbolines as Inhibitors of Haspin and DYRK Kinases

Jonathan M.G. Higgins; Debasis Patnaik; Natalia P. Ulyanova; Ross L. Stein; Jun Xian; Marcie A. Glicksman; Gregory D. Cuny


Archive | 2011

Small molecule inhibitors of usp1 deubiquitinating enzyme activity

Alan D. D'Andrea; Gregory D. Cuny; Ross L. Stein; Marcie A. Glicksman; April Case; Jun Xian; David Wilson; Min Huang


Archive | 2011

ACRIDINES AS INHIBITORS OF HASPIN AND DYRK KINASES

Jonathan M.G. Higgins; Gregory D. Cuny; Marcie A. Glicksman; Debasis Patnaik; Maxime Robin; Ross L. Stein; Jun Xian


Archive | 2010

PHOSPHATIDYLCHOLINE TRANSFER PROTEIN INHIBITORS

David E. Cohen; Neil Wagle; Gregory D. Cuny; Jun Xian; Marcie A. Glicksman; Ross L. Stein; Ekaterina Y. Shishova

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Marcie A. Glicksman

Brigham and Women's Hospital

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Ross L. Stein

Brigham and Women's Hospital

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Debasis Patnaik

Brigham and Women's Hospital

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Natalia P. Ulyanova

Brigham and Women's Hospital

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