15 results on '"Ada Chen"'
Search Results
2. 583 Novel, potent, and selective inhibitors of hypoxia-inducible factor (HIF)-2α reverse pro-tumorigenic transcriptional programming in cancer, stromal, and immune cells
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Matthew Walters, Stephen Young, Ada Chen, Akshata Udyavar, Kelsey Sivick Gauthier, Dana Piovesan, Kenneth Lawson, Soonweng Cho, Jean Chan, Jennie Au, Cesar Meleza, Xiaoning Zhao, Anh Tran, Samuel Drew, Balint Gal, Brandon Rosen, Manmohan Leleti, Elaine Ginn, Lixia Jin, and Jay Powers more...
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
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Catalog
3. Discovery of Potent and Selective Methylenephosphonic Acid CD73 Inhibitors
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Dillon H. Miles, Nigel Walker, Manmohan Reddy Leleti, Xiaoning Zhao, Eric T. Newcomb, Kenneth V. Lawson, Jaroslaw Kalisiak, Erick Allen Lindsey, Lixia Jin, Ada Chen, Laurent Debien, Guifen Xu, Ehesan U. Sharif, Norbert Sträter, Brandon Reid Rosen, Stephen W Young, Emma Scaletti, and Jay P. Powers more...
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Adenosine ,Phosphorous Acids ,Drug Evaluation, Preclinical ,Molecular Dynamics Simulation ,Crystallography, X-Ray ,GPI-Linked Proteins ,01 natural sciences ,Structure-Activity Relationship ,03 medical and health sciences ,Immune system ,ATP hydrolysis ,Drug Discovery ,medicine ,Extracellular ,Humans ,Ectonucleotidase ,5'-Nucleotidase ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Tumor microenvironment ,Binding Sites ,Adenosine receptor ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Enzyme ,chemistry ,Biochemistry ,Drug Design ,Molecular Medicine ,medicine.drug - Abstract
Solid tumors are often associated with high levels of extracellular ATP. Ectonucleotidases catalyze the sequential hydrolysis of ATP to adenosine, which potently suppresses T-cell and NK-cell functions via the adenosine receptors (A2a and A2b). The ectonucleotidase CD73 catalyzes the conversion of AMP to adenosine. Thus, increased CD73 enzymatic activity in the tumor microenvironment is a potential mechanism for tumor immune evasion and has been associated with poor prognosis in the clinic. CD73 inhibition is anticipated to restore immune function by skirting this major mechanism of adenosine generation. We have developed a series of potent and selective methylenephosphonic acid CD73 inhibitors via a structure-based design. Key binding interactions of the known inhibitor adenosine-5'-(α,β-methylene)diphosphate (AMPCP) with hCD73 provided the foundation for our early designs. The structure-activity relationship study guided by this structure-based design led to the discovery of 4a, which exhibits excellent potency against CD73, exquisite selectivity against related ectonucleotidases, and a favorable pharmacokinetic profile. more...
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- 2021
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4. Discovery of Potent and Selective PI3Kγ Inhibitors
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Dillon H. Miles, Ada Chen, Manmohan Reddy Leleti, Divyank Soni, Stephen W Young, Artur K. Mailyan, Kenneth V. Lawson, Stefan G Shaqfeh, Ehesan U. Sharif, Pei-Yu Chen, Jenna L. Jeffrey, Jesus Banuelos, Xuelei Yan, Samuel L Drew, Nigel Walker, Puja Dhanota, Lixia Jin, Jay P. Powers, Elaine Ginn, Guillaume Mata, Kent Wong, Jeremy Fournier, Joel W. Beatty, Rhiannon Thomas-Tran, Ulrike Schindler, Amber Pham, Matthew J. Walters, Jie Chen, Cesar Meleza, and Xiaoning Zhao more...
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Gene isoform ,Stereochemistry ,Crystallography, X-Ray ,01 natural sciences ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Discovery ,Animals ,Class Ib Phosphatidylinositol 3-Kinase ,Humans ,Binding site ,Phosphoinositide-3 Kinase Inhibitors ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Trifluoromethyl ,Bicyclic molecule ,Lipid signaling ,Rats ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Enzyme ,chemistry ,Drug Design ,Molecular Medicine ,Selectivity ,Adenosine triphosphate - Abstract
The selective inhibition of the lipid signaling enzyme PI3Kγ constitutes an opportunity to mediate immunosuppression and inflammation within the tumor microenvironment but is difficult to achieve due to the high sequence homology across the class I PI3K isoforms. Here, we describe the design of a novel series of potent PI3Kγ inhibitors that attain high isoform selectivity through the divergent projection of substituents into both the "selectivity" and "alkyl-induced" pockets within the adenosine triphosphate (ATP) binding site of PI3Kγ. These efforts have culminated in the discovery of 5-[2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-[(1S)-1-cyclopropylethyl]-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (4, IC50 = 0.064 μM, THP-1 cells), which displays >600-fold selectivity for PI3Kγ over the other class I isoforms and is a promising step toward the identification of a clinical development candidate. The structure-activity relationships identified throughout this campaign demonstrate that greater γ-selectivity can be achieved by inhibitors that occupy an "alkyl-induced" pocket and possess bicyclic hinge-binding motifs capable of forming more than one hydrogen bond to the hinge region of PI3Kγ. more...
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- 2020
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5. Discovery of AB680: A Potent and Selective Inhibitor of CD73
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Brandon Reid Rosen, Manmohan Reddy Leleti, Ada Chen, Sharon Zhao, Jenna L. Jeffrey, Norbert Sträter, Eric T. Newcomb, Jay P. Powers, Kenneth V. Lawson, Lijuan Fu, Dillon H. Miles, Uli Schindler, Wade Berry, Stephen W Young, Tim Park, Emma Scaletti, Lixia Jin, Joanne B.L. Tan, Ehesan U. Sharif, Laurent Debien, Erick Allen Lindsey, Jaroslaw Kalisiak, Susanne Moschütz, Matthew J. Walters, Guifen Xu, and Nigel Walker more...
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Models, Molecular ,T cell ,CD8-Positive T-Lymphocytes ,Pharmacology ,GPI-Linked Proteins ,01 natural sciences ,Small Molecule Libraries ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,Immune system ,Pharmacokinetics ,Drug Discovery ,medicine ,Extracellular ,Animals ,Humans ,Structure–activity relationship ,5'-Nucleotidase ,030304 developmental biology ,0303 health sciences ,Tumor microenvironment ,Binding Sites ,Chemistry ,Catabolism ,Haplorhini ,Adenosine ,Rats ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,medicine.anatomical_structure ,Leukocytes, Mononuclear ,Molecular Medicine ,Protein Binding ,medicine.drug - Abstract
Extracellular adenosine (ADO), present in high concentrations in the tumor microenvironment (TME), suppresses immune function via inhibition of T cell and NK cell activation. Intratumoral generation of ADO depends on the sequential catabolism of ATP by two ecto-nucleotidases, CD39 (ATP → AMP) and CD73 (AMP → ADO). Inhibition of CD73 eliminates a major pathway of ADO production in the TME and can reverse ADO-mediated immune suppression. Extensive interrogation of structure-activity relationships (SARs), structure-based drug design, and optimization of pharmacokinetic properties culminated in the discovery of AB680, a highly potent (Ki = 5 pM), reversible, and selective inhibitor of CD73. AB680 is further characterized by very low clearance and long half-lives across preclinical species, resulting in a PK profile suitable for long-acting parenteral administration. AB680 is currently being evaluated in phase 1 clinical trials. Initial data show AB680 is well tolerated and exhibits a pharmacokinetic profile suitable for biweekly (Q2W) iv-administration in human. more...
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- 2020
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6. Evaluating the ICF Framework as a Model of Community Participation for People with Disabilities
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Ada Chen
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Rehabilitation ,Physical Therapy, Sports Therapy and Rehabilitation - Published
- 2022
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7. Design, Synthesis, and Structure-Activity Relationship Optimization of Pyrazolopyrimidine Amide Inhibitors of Phosphoinositide 3-Kinase γ (PI3Kγ).
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Mata, Guillaume, Miles, Dillon H., Drew, Samuel L., Fournier, Jeremy, Lawson, Kenneth V., Mailyan, Artur K., Sharif, Ehesan U., Xuelei Yan, Beatty, Joel W., Banuelos, Jesus, Jie Chen, Ginn, Elaine, Ada Chen, Gerrick, Kimberline Y., Pham, Amber T., Wong, Kent, Soni, Divyank, Dhanota, Puja, Shaqfeh, Stefan G., and Meleza, Cesar more...
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- 2022
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8. Assessment of the Integrity of Compounds Stored in Assay-Ready Plates Using a Kinase Sentinel Assay
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Shou-Hua Xiao, Cheng Su, Yichin Liu, John D. McCarter, Leeanne Zalameda, Thim Oung, Son Dang, Ada Chen, Xiaoning Zhao, Stephen W. Young, Xiaoyang Xia, Amanda Lembke, Heather Eastwood, and Laina Mercer more...
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Chromatography ,Chemistry ,Drug Storage ,Organic Chemistry ,Analytical chemistry ,Compound management ,Fraction (chemistry) ,General Medicine ,Mass Spectrometry ,Lower temperature ,Computer Science Applications ,Solvent ,Drug Stability ,Drug Discovery ,Solvents ,Potency ,Dimethyl Sulfoxide ,A kinase ,Chromatography, Liquid - Abstract
Sentinel assays are a convenient adjunct to LC-MS purity assessment to monitor the integrity of compounds in pharmaceutical screening collections over time. To assess the stability of compounds stored both at room temperature and at -20°C in assay-ready plates that were either vacuum pack-sealed using a convenient industrial vacuum sealing method or individually sealed using conventional foil seals, a diverse collection of#126; 5,000 compounds was assayed using a robust biochemical kinase assay at intervals over a one year period. Assay results at each time point were compared to those of initial assay using a series of correlations of compound Percent of Control (POC) values as well as IC50 values of a subset of compounds in 200 nL or 500 nL plates. The fraction of hits in common between initial assays and assays at later time points ranged from 82% to 95% over one year and remained relatively constant over time with all storage temperatures or sealing methods tested. A majority of the hits that exhibited a consistent gradual trend to lower potency over one year storage were shifted to lower potency upon the rapid removal of DMSO solvent. Compound precipitation rather than compound decomposition is the likely reason for trends to lower potency for most such compounds over the storage period. Plates stored at room temperature featured a significantly higher fraction of hits that exhibited a trend to lower apparent potency than those stored at -20°C suggesting that this lower temperature is preferable for longer-term storage. more...
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- 2013
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9. Safeguard gaps and their managerial issues
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Wan-Ying Lin, Rua-Huan Tsaih, and Ada Chen
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Value (ethics) ,Knowledge management ,Process (engineering) ,business.industry ,Business process ,Strategy and Management ,Data security ,Information security ,Industrial and Manufacturing Engineering ,Computer Science Applications ,Management Information Systems ,Safeguard ,Loan ,Industrial relations ,Business ,Marketing ,Information exchange - Abstract
PurposeTargeting the information security issue related to a bank loan process, this study aims to explore an approach that is user‐friendly to non‐information technology managers to be actively participative in the process of investigating the underlying information‐processing infrastructure.Design/methodology/approachA case study approach is used to analyze the safeguard gaps between the physical information assets (IAs) of a business process and their digital counterparts.FindingsThis study shows the existence of safeguard gaps between the physical IAs of a business process and their digital counterparts, explores a way of investigating such gaps, and provides (detection‐ and prevention‐oriented) managerial proposals to cope with the safeguard gap issue.Originality/valueThe existence of safeguard gaps releases (warning) signal to executives and executives should consult managers on how to manage these safeguard gaps. There are two types of managerial proposals to cope with the safeguard gap issue. The detection‐oriented proposals aim at ensuring early detection and interception of security breaches;, e.g. setting up a cross‐audit function to discover the security breaches. The prevention‐oriented proposals aim at alleviating the safeguard gaps;, e.g. re‐designing the processes of operation management and the associated risk management. more...
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- 2008
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10. Maternal immune activation alters placental histone-3 lysine-9 tri-methylation, offspring sensorimotor processing, and hypothalamic transposable element expression in a sex-specific manner
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Holly DeRosa, Arianna Smith, Laurel Geist, Ada Cheng, Richard G. Hunter, and Amanda C. Kentner
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Maternal immune activation ,Retrotransposons ,Transposable elements ,Epigenetics ,Placenta ,Prepulse inhibition ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 ,Neurophysiology and neuropsychology ,QP351-495 - Abstract
Animal models of maternal immune activation (MIA) are central to identifying the biological mechanisms that underly the association between prenatal infection and neuropsychiatric disorder susceptibility. Many studies, however, have limited their scope to protein coding genes and their role in mediating this inherent risk, while much less attention has been directed towards exploring the roles of the epigenome and transposable elements (TEs). In Experiment 1, we demonstrate the ability of MIA to alter the chromatin landscape of the placenta. We induced MIA by injecting 200 μg/kg (i.p.) of lipopolysaccharide (LPS) on gestational day 15 in Sprague-Dawley rats. We found a sex-specific rearrangement of heterochromatin 24-h after exposure to MIA, as evidenced by an increase in histone-3 lysine-9 trimethylation (H3K9me3). In Experiment 2, MIA was associated with long-term sensorimotor processing deficits as indicated by reduced prepulse inhibition (PPI) of the acoustic startle reflex in adult male and female offspring and an increased mechanical allodynia threshold in males. Analyses of gene expression within the hypothalamus-chosen for its involvement in the sex-specific pathogenesis of schizophrenia and the stress response-revealed significantly higher levels of the stress-sensitive genes Gr and Fkbp5. Deleterious TE expression is often a hallmark of neuropsychiatric disease and we found sex-specific increases in the expression of several TEs including IAP, B2 SINE, and LINE-1 ORF1. The data from this study warrant the future consideration of chromatin stability and TEs as part of the mechanism that drives MIA-associated changes in the brain and behavior. more...
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- 2023
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11. WET GROWTH: EFFECTS OF WATER POLICIES ON LAND USE IN THE AMERICAN WEST
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Ada Chen and Ellen Hanak
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Water conservation ,Land use ,Natural resource economics ,restrict ,Economics ,Population growth ,Environmental Science (miscellaneous) ,Development ,Water resource management ,American west ,Groundwater ,Externality ,Water trading - Abstract
Rapid population growth and increasing water development costs have prompted many western governments to condition residential development approval on the adequacy of water supplies. We examine the effects of these regulations on housing supply in Colorado and New Mexico using fixed-effects panel regressions. Our findings suggest that price-based tools to ensure water availability may be a preferred regulatory alternative to quantity restrictions. Attempts to restrict groundwater basin access have not unambiguously corrected negative externalities related to growth. Meanwhile, Colorado cities' aggressive use of impact fees has facilitated water resource development, without limiting growth. more...
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- 2007
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12. Methylation in hMLH1 promoter interferes with its binding to transcription factor CBF and inhibits gene expression
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Ada Chen, Guoren Deng, Young S. Kim, and Erik Weiking Pong
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congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,Transcription, Genetic ,Recombinant Fusion Proteins ,Response element ,CAAT box ,Adenocarcinoma ,Biology ,Decitabine ,Transfection ,Epigenetics of physical exercise ,Genes, Reporter ,Transcription (biology) ,Tumor Cells, Cultured ,Genetics ,Humans ,Gene Silencing ,Luciferases ,Promoter Regions, Genetic ,neoplasms ,Molecular Biology ,Transcription factor ,Adaptor Proteins, Signal Transducing ,Binding Sites ,Nuclear Proteins ,nutritional and metabolic diseases ,Promoter ,DNA, Neoplasm ,Methylation ,DNA Methylation ,Molecular biology ,digestive system diseases ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,CCAAT-Binding Factor ,Gene Expression Regulation ,DNA methylation ,Azacitidine ,CpG Islands ,Electrophoresis, Polyacrylamide Gel ,Carrier Proteins ,Colorectal Neoplasms ,MutL Protein Homolog 1 ,Protein Binding - Abstract
Microsatellite instability (MSI) is caused by the dysfunction of mismatch repair genes, such as hMLH1, hMSH2. Loss of hMLH1 expression and methylation of CpG sites in hMLH1 promoter are frequently present in sporadic colorectal cancer with MSI. In this study, by transient transfection assay with constructs containing different lengths of hMLH1 promoter and a luciferase reporter gene, we located a proximal region of hMLH1 promoter, which plays a main role in regulating the gene. The fact that luciferase activities were high in all host cell lines regardless of their hMLH1 expression levels indicates that the transcription machinery is intact even in non-expressing cells. When hMLH1 promoter was in vitro methylated before transfection, the luciferase activities in the transfectants were significantly reduced. This observation indicates that methylation causes the inhibition of hMLH1 promoter activity. By electrophoretic mobility shift assay (EMSA), we identified a CCAAT box in this region, which specifically bound transcription factor CBF. Mutations in CCAAT box not only inhibited its binding to CBF factor, but also reduced its ability to drive the expression of luciferase gene. The role of CBF in activating transcription was further substantiated by inhibition of promoter activity with a plasmid expressing a dominant negative CBF-B mutant. Methylation at a CpG site two base pairs upstream of the CCAAT box inhibited the binding of CBF to CCAAT box. We conclude that methylation of an adjacent CpG site inhibits binding of the CBF transcription to the corresponding CCAAT box, and is one of the causes of hMLH1 gene silencing in colon cancer cells. more...
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- 2001
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13. The adoption of virtual banking: an empirical study
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Huaiqing Wang, Yuan Pu Shao, S. Y. Liao, and Ada Chen
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Strategic planning ,Hardware_MEMORYSTRUCTURES ,Computer Networks and Communications ,business.industry ,Theory of planned behavior ,Information technology ,Library and Information Sciences ,Virtual reality ,Empirical research ,Telephone banking ,Retail banking ,The Internet ,Business ,Marketing ,Information Systems - Abstract
Virtual banking is broadly defined in this paper as the provision of banking services via means other than traditional physical branches. Currently, virtual banking exists in the forms of ATM, phone banking, home banking and Internet banking. Understanding people's adoption intention of virtual banking can help financial institutions to formulate appropriate marketing strategies for new forms of banking. Theory of planned behavior (TPB) and innovation diffusion were used to study the adoption intention of virtual banking in a well-developed international financial city. The study finds that the relationships were found only partially explained by the TPB. Other results are interesting and useful for the strategic planning of IT in banking. more...
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- 1999
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14. Safeguard gaps and their managerial issues.
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Rua-Huan Tsaih, Wan-Ying Lin, and Ada Chen
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BANK loans ,BANK security ,INFRASTRUCTURE (Economics) ,COMMERCIAL credit ,BUSINESS process outsourcing ,PRODUCT management ,DISCRIMINATION in consumer credit ,RISK exposure ,INFORMATION technology - Abstract
Purpose - Targeting the information security issue related to a bank loan process, this study aims to explore an approach that is user-friendly to non-information technology managers to be actively participative in the process of investigating the underlying information-processing infrastructure. Design/methodology/approach - A case study approach is used to analyze the safeguard gaps between the physical information assets (lAs) of a business process and their digital counterparts. Findings - This study shows the existence of safeguard gaps between the physical lAs of a business process and their digital counterparts, explores a way of investigating such gaps, and provides (detection- and prevention-oriented) managerial proposals to cope with the safeguard gap issue. Originality/value - The existence of safeguard gaps releases (warning) signal to executives and executives should consult managers on how to manage these safeguard gaps. There are two types of managerial proposals to cope with the safeguard gap issue. The detection-oriented proposals aim at ensuring early detection and interception of security breaches;, e.g. setting up a cross-audit function to discover the security breaches. The prevention-oriented proposals aim at alleviating the safeguard gaps;, e.g. re-designing the processes of operation management and the associated risk management. [ABSTRACT FROM AUTHOR] more...
- Published
- 2008
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15. Chemical Genetics of Rapamycin-Insensitive TORC2 in S. cerevisiae
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Joseph I. Kliegman, Dorothea Fiedler, Colm J. Ryan, Yi-Fan Xu, Xiao-yang Su, David Thomas, Max C. Caccese, Ada Cheng, Michael Shales, Joshua D. Rabinowitz, Nevan J. Krogan, and Kevan M. Shokat
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Biology (General) ,QH301-705.5 - Abstract
Current approaches for identifying synergistic targets use cell culture models to see if the combined effect of clinically available drugs is better than predicted by their individual efficacy. New techniques are needed to systematically and rationally identify targets and pathways that may be synergistic targets. Here, we created a tool to screen and identify molecular targets that may synergize with new inhibitors of target of rapamycin (TOR), a conserved protein that is a major integrator of cell proliferation signals in the nutrient-signaling pathway. Although clinical results from TOR complex 1 (TORC1)-specific inhibition using rapamycin analogs have been disappointing, trials using inhibitors that also target TORC2 have been promising. To understand this increased therapeutic efficacy and to discover secondary targets for combination therapy, we engineered Tor2 in S. cerevisiae to accept an orthogonal inhibitor. We used this tool to create a chemical epistasis miniarray profile (ChE-MAP) by measuring interactions between the chemically inhibited Tor2 kinase and a diverse library of deletion mutants. The ChE-MAP identified known TOR components and distinguished between TORC1- and TORC2-dependent functions. The results showed a TORC2-specific interaction with the pentose phosphate pathway, a previously unappreciated TORC2 function that suggests a role for the complex in balancing the high energy demand required for ribosome biogenesis. more...
- Published
- 2013
- Full Text
- View/download PDF
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