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2. AKT-mTORC1 reactivation is the dominant resistance driver for PI3Kβ/AKT inhibitors in PTEN-null breast cancer and can be overcome by combining with Mcl-1 inhibitors

Author

Dunn, Shanade, Eberlein, Cath, Yu, Jason, Gris-Oliver, Albert, Ong, Swee Hoe, Yelland, Urs, Cureton, Natalie, Staniszewska, Anna, McEwen, Robert, Fox, Millie, Pilling, James, Hopcroft, Philip, Coker, Elizabeth A., Jaaks, Patricia, Garnett, Mathew J., Isherwood, Beverley, Serra, Violeta, Davies, Barry R., Barry, Simon T., Lynch, James T., and Yusa, Kosuke

Published
2022
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3. Table S4 from Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations

Author

Bashi, Azadeh C., primary, Coker, Elizabeth A., primary, Bulusu, Krishna C., primary, Jaaks, Patricia, primary, Crafter, Claire, primary, Lightfoot, Howard, primary, Milo, Marta, primary, McCarten, Katrina, primary, Jenkins, David F., primary, van der Meer, Dieudonne, primary, Lynch, James T., primary, Barthorpe, Syd, primary, Andersen, Courtney L., primary, Barry, Simon T., primary, Beck, Alexandra, primary, Cidado, Justin, primary, Gordon, Jacob A., primary, Hall, Caitlin, primary, Hall, James, primary, Mali, Iman, primary, Mironenko, Tatiana, primary, Mongeon, Kevin, primary, Morris, James, primary, Richardson, Laura, primary, Smith, Paul D., primary, Tavana, Omid, primary, Tolley, Charlotte, primary, Thomas, Frances, primary, Willis, Brandon S., primary, Yang, Wanjuan, primary, O'Connor, Mark J., primary, McDermott, Ultan, primary, Critchlow, Susan E., primary, Drew, Lisa, primary, Fawell, Stephen E., primary, Mettetal, Jerome T., primary, and Garnett, Mathew J., primary

Published
2024
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4. Figure 6 from Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations

Author

Bashi, Azadeh C., primary, Coker, Elizabeth A., primary, Bulusu, Krishna C., primary, Jaaks, Patricia, primary, Crafter, Claire, primary, Lightfoot, Howard, primary, Milo, Marta, primary, McCarten, Katrina, primary, Jenkins, David F., primary, van der Meer, Dieudonne, primary, Lynch, James T., primary, Barthorpe, Syd, primary, Andersen, Courtney L., primary, Barry, Simon T., primary, Beck, Alexandra, primary, Cidado, Justin, primary, Gordon, Jacob A., primary, Hall, Caitlin, primary, Hall, James, primary, Mali, Iman, primary, Mironenko, Tatiana, primary, Mongeon, Kevin, primary, Morris, James, primary, Richardson, Laura, primary, Smith, Paul D., primary, Tavana, Omid, primary, Tolley, Charlotte, primary, Thomas, Frances, primary, Willis, Brandon S., primary, Yang, Wanjuan, primary, O'Connor, Mark J., primary, McDermott, Ultan, primary, Critchlow, Susan E., primary, Drew, Lisa, primary, Fawell, Stephen E., primary, Mettetal, Jerome T., primary, and Garnett, Mathew J., primary

Published
2024
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5. Supplementary Figures S1-S16 from Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations

Author

Bashi, Azadeh C., primary, Coker, Elizabeth A., primary, Bulusu, Krishna C., primary, Jaaks, Patricia, primary, Crafter, Claire, primary, Lightfoot, Howard, primary, Milo, Marta, primary, McCarten, Katrina, primary, Jenkins, David F., primary, van der Meer, Dieudonne, primary, Lynch, James T., primary, Barthorpe, Syd, primary, Andersen, Courtney L., primary, Barry, Simon T., primary, Beck, Alexandra, primary, Cidado, Justin, primary, Gordon, Jacob A., primary, Hall, Caitlin, primary, Hall, James, primary, Mali, Iman, primary, Mironenko, Tatiana, primary, Mongeon, Kevin, primary, Morris, James, primary, Richardson, Laura, primary, Smith, Paul D., primary, Tavana, Omid, primary, Tolley, Charlotte, primary, Thomas, Frances, primary, Willis, Brandon S., primary, Yang, Wanjuan, primary, O'Connor, Mark J., primary, McDermott, Ultan, primary, Critchlow, Susan E., primary, Drew, Lisa, primary, Fawell, Stephen E., primary, Mettetal, Jerome T., primary, and Garnett, Mathew J., primary

Published
2024
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6. Figure 5 from Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations

Author

Bashi, Azadeh C., primary, Coker, Elizabeth A., primary, Bulusu, Krishna C., primary, Jaaks, Patricia, primary, Crafter, Claire, primary, Lightfoot, Howard, primary, Milo, Marta, primary, McCarten, Katrina, primary, Jenkins, David F., primary, van der Meer, Dieudonne, primary, Lynch, James T., primary, Barthorpe, Syd, primary, Andersen, Courtney L., primary, Barry, Simon T., primary, Beck, Alexandra, primary, Cidado, Justin, primary, Gordon, Jacob A., primary, Hall, Caitlin, primary, Hall, James, primary, Mali, Iman, primary, Mironenko, Tatiana, primary, Mongeon, Kevin, primary, Morris, James, primary, Richardson, Laura, primary, Smith, Paul D., primary, Tavana, Omid, primary, Tolley, Charlotte, primary, Thomas, Frances, primary, Willis, Brandon S., primary, Yang, Wanjuan, primary, O'Connor, Mark J., primary, McDermott, Ultan, primary, Critchlow, Susan E., primary, Drew, Lisa, primary, Fawell, Stephen E., primary, Mettetal, Jerome T., primary, and Garnett, Mathew J., primary

Published
2024
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7. Figure 3 from Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations

Author

Bashi, Azadeh C., primary, Coker, Elizabeth A., primary, Bulusu, Krishna C., primary, Jaaks, Patricia, primary, Crafter, Claire, primary, Lightfoot, Howard, primary, Milo, Marta, primary, McCarten, Katrina, primary, Jenkins, David F., primary, van der Meer, Dieudonne, primary, Lynch, James T., primary, Barthorpe, Syd, primary, Andersen, Courtney L., primary, Barry, Simon T., primary, Beck, Alexandra, primary, Cidado, Justin, primary, Gordon, Jacob A., primary, Hall, Caitlin, primary, Hall, James, primary, Mali, Iman, primary, Mironenko, Tatiana, primary, Mongeon, Kevin, primary, Morris, James, primary, Richardson, Laura, primary, Smith, Paul D., primary, Tavana, Omid, primary, Tolley, Charlotte, primary, Thomas, Frances, primary, Willis, Brandon S., primary, Yang, Wanjuan, primary, O'Connor, Mark J., primary, McDermott, Ultan, primary, Critchlow, Susan E., primary, Drew, Lisa, primary, Fawell, Stephen E., primary, Mettetal, Jerome T., primary, and Garnett, Mathew J., primary

Published
2024
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8. Figure 1 from Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations

Author

Bashi, Azadeh C., primary, Coker, Elizabeth A., primary, Bulusu, Krishna C., primary, Jaaks, Patricia, primary, Crafter, Claire, primary, Lightfoot, Howard, primary, Milo, Marta, primary, McCarten, Katrina, primary, Jenkins, David F., primary, van der Meer, Dieudonne, primary, Lynch, James T., primary, Barthorpe, Syd, primary, Andersen, Courtney L., primary, Barry, Simon T., primary, Beck, Alexandra, primary, Cidado, Justin, primary, Gordon, Jacob A., primary, Hall, Caitlin, primary, Hall, James, primary, Mali, Iman, primary, Mironenko, Tatiana, primary, Mongeon, Kevin, primary, Morris, James, primary, Richardson, Laura, primary, Smith, Paul D., primary, Tavana, Omid, primary, Tolley, Charlotte, primary, Thomas, Frances, primary, Willis, Brandon S., primary, Yang, Wanjuan, primary, O'Connor, Mark J., primary, McDermott, Ultan, primary, Critchlow, Susan E., primary, Drew, Lisa, primary, Fawell, Stephen E., primary, Mettetal, Jerome T., primary, and Garnett, Mathew J., primary

Published
2024
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9. Supplementary Tables from Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations

Author

Bashi, Azadeh C., primary, Coker, Elizabeth A., primary, Bulusu, Krishna C., primary, Jaaks, Patricia, primary, Crafter, Claire, primary, Lightfoot, Howard, primary, Milo, Marta, primary, McCarten, Katrina, primary, Jenkins, David F., primary, van der Meer, Dieudonne, primary, Lynch, James T., primary, Barthorpe, Syd, primary, Andersen, Courtney L., primary, Barry, Simon T., primary, Beck, Alexandra, primary, Cidado, Justin, primary, Gordon, Jacob A., primary, Hall, Caitlin, primary, Hall, James, primary, Mali, Iman, primary, Mironenko, Tatiana, primary, Mongeon, Kevin, primary, Morris, James, primary, Richardson, Laura, primary, Smith, Paul D., primary, Tavana, Omid, primary, Tolley, Charlotte, primary, Thomas, Frances, primary, Willis, Brandon S., primary, Yang, Wanjuan, primary, O'Connor, Mark J., primary, McDermott, Ultan, primary, Critchlow, Susan E., primary, Drew, Lisa, primary, Fawell, Stephen E., primary, Mettetal, Jerome T., primary, and Garnett, Mathew J., primary

Published
2024
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10. Figure 4 from Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations

Author

Bashi, Azadeh C., primary, Coker, Elizabeth A., primary, Bulusu, Krishna C., primary, Jaaks, Patricia, primary, Crafter, Claire, primary, Lightfoot, Howard, primary, Milo, Marta, primary, McCarten, Katrina, primary, Jenkins, David F., primary, van der Meer, Dieudonne, primary, Lynch, James T., primary, Barthorpe, Syd, primary, Andersen, Courtney L., primary, Barry, Simon T., primary, Beck, Alexandra, primary, Cidado, Justin, primary, Gordon, Jacob A., primary, Hall, Caitlin, primary, Hall, James, primary, Mali, Iman, primary, Mironenko, Tatiana, primary, Mongeon, Kevin, primary, Morris, James, primary, Richardson, Laura, primary, Smith, Paul D., primary, Tavana, Omid, primary, Tolley, Charlotte, primary, Thomas, Frances, primary, Willis, Brandon S., primary, Yang, Wanjuan, primary, O'Connor, Mark J., primary, McDermott, Ultan, primary, Critchlow, Susan E., primary, Drew, Lisa, primary, Fawell, Stephen E., primary, Mettetal, Jerome T., primary, and Garnett, Mathew J., primary

Published
2024
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11. Data from Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations

Author

Bashi, Azadeh C., primary, Coker, Elizabeth A., primary, Bulusu, Krishna C., primary, Jaaks, Patricia, primary, Crafter, Claire, primary, Lightfoot, Howard, primary, Milo, Marta, primary, McCarten, Katrina, primary, Jenkins, David F., primary, van der Meer, Dieudonne, primary, Lynch, James T., primary, Barthorpe, Syd, primary, Andersen, Courtney L., primary, Barry, Simon T., primary, Beck, Alexandra, primary, Cidado, Justin, primary, Gordon, Jacob A., primary, Hall, Caitlin, primary, Hall, James, primary, Mali, Iman, primary, Mironenko, Tatiana, primary, Mongeon, Kevin, primary, Morris, James, primary, Richardson, Laura, primary, Smith, Paul D., primary, Tavana, Omid, primary, Tolley, Charlotte, primary, Thomas, Frances, primary, Willis, Brandon S., primary, Yang, Wanjuan, primary, O'Connor, Mark J., primary, McDermott, Ultan, primary, Critchlow, Susan E., primary, Drew, Lisa, primary, Fawell, Stephen E., primary, Mettetal, Jerome T., primary, and Garnett, Mathew J., primary

Published
2024
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12. Figure 2 from Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations

Author

Bashi, Azadeh C., primary, Coker, Elizabeth A., primary, Bulusu, Krishna C., primary, Jaaks, Patricia, primary, Crafter, Claire, primary, Lightfoot, Howard, primary, Milo, Marta, primary, McCarten, Katrina, primary, Jenkins, David F., primary, van der Meer, Dieudonne, primary, Lynch, James T., primary, Barthorpe, Syd, primary, Andersen, Courtney L., primary, Barry, Simon T., primary, Beck, Alexandra, primary, Cidado, Justin, primary, Gordon, Jacob A., primary, Hall, Caitlin, primary, Hall, James, primary, Mali, Iman, primary, Mironenko, Tatiana, primary, Mongeon, Kevin, primary, Morris, James, primary, Richardson, Laura, primary, Smith, Paul D., primary, Tavana, Omid, primary, Tolley, Charlotte, primary, Thomas, Frances, primary, Willis, Brandon S., primary, Yang, Wanjuan, primary, O'Connor, Mark J., primary, McDermott, Ultan, primary, Critchlow, Susan E., primary, Drew, Lisa, primary, Fawell, Stephen E., primary, Mettetal, Jerome T., primary, and Garnett, Mathew J., primary

Published
2024
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13. Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations

Author

Bashi, Azadeh C., primary, Coker, Elizabeth A., additional, Bulusu, Krishna C., additional, Jaaks, Patricia, additional, Crafter, Claire, additional, Lightfoot, Howard, additional, Milo, Marta, additional, McCarten, Katrina, additional, Jenkins, David F., additional, van der Meer, Dieudonne, additional, Lynch, James T., additional, Barthorpe, Syd, additional, Andersen, Courtney L., additional, Barry, Simon T., additional, Beck, Alexandra, additional, Cidado, Justin, additional, Gordon, Jacob A., additional, Hall, Caitlin, additional, Hall, James, additional, Mali, Iman, additional, Mironenko, Tatiana, additional, Mongeon, Kevin, additional, Morris, James, additional, Richardson, Laura, additional, Smith, Paul D., additional, Tavana, Omid, additional, Tolley, Charlotte, additional, Thomas, Frances, additional, Willis, Brandon S., additional, Yang, Wanjuan, additional, O'Connor, Mark J., additional, McDermott, Ultan, additional, Critchlow, Susan E., additional, Drew, Lisa, additional, Fawell, Stephen E., additional, Mettetal, Jerome T., additional, and Garnett, Mathew J., additional

Published
2024
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14. Development of a Series of Pyrrolopyridone MAT2A Inhibitors.

Author

Atkinson, Stephen J., Bagal, Sharan K., Argyrou, Argyrides, Askin, Sean, Cheung, Tony, Chiarparin, Elisabetta, Coen, Muireann, Collie, Iain T., Dale, Ian L., De Fusco, Claudia, Dillman, Keith, Evans, Laura, Feron, Lyman J., Foster, Alison J., Grondine, Michael, Kantae, Vasudev, Lamont, Gillian M., Lamont, Scott, Lynch, James T., and Nilsson Lill, Sten

Published
2024
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15. Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL

Author

Erdmann, Tabea, Klener, Pavel, Lynch, James T., Grau, Michael, Vočková, Petra, Molinsky, Jan, Tuskova, Diana, Hudson, Kevin, Polanska, Urszula M., Grondine, Michael, Mayo, Michele, Dai, Beiying, Pfeifer, Matthias, Erdmann, Kristian, Schwammbach, Daniela, Zapukhlyak, Myroslav, Staiger, Annette M., Ott, German, Berdel, Wolfgang E., Davies, Barry R., Cruzalegui, Francisco, Trneny, Marek, Lenz, Peter, Barry, Simon T., and Lenz, Georg

Published
2017
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16. Abstract 6272: AZ-PRMT5i-1: A potent MTAP-selective PRMT5 inhibitor with pharmacodynamic and monotherapy anti-tumor activity in MTAP-deleted tumours

Author

Lynch, James T., primary, Moore, Shaun, additional, Barrantes, Ivan Del Barco, additional, Bradshaw, Lauren, additional, Chambers, Chris, additional, Hong, Ted, additional, Cooke, Sophie, additional, Urosevic, Jelena, additional, Vazquez-Chantada, Mercedes, additional, Smith, James M., additional, Cronin, Anna, additional, Recolin, Benedicte, additional, Gill, Sonja, additional, Critchlow, Susan, additional, Chan, Ho Man, additional, and Dean, Emma, additional

Published
2023
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17. Data from Combined Inhibition of PI3Kβ and mTOR Inhibits Growth of PTEN-null Tumors

Author

Lynch, James T., primary, Polanska, Urszula M., primary, Hancox, Ursula, primary, Delpuech, Oona, primary, Maynard, Juliana, primary, Trigwell, Catherine, primary, Eberlein, Catherine, primary, Lenaghan, Carol, primary, Polanski, Radoslaw, primary, Avivar-Valderas, Alvaro, primary, Cumberbatch, Marie, primary, Klinowska, Teresa, primary, Critchlow, Susan E., primary, Cruzalegui, Francisco, primary, and Barry, Simon T., primary

Published
2023
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18. Supplementary Tables 1-3 from Combined Inhibition of PI3Kβ and mTOR Inhibits Growth of PTEN-null Tumors

Author

Lynch, James T., primary, Polanska, Urszula M., primary, Hancox, Ursula, primary, Delpuech, Oona, primary, Maynard, Juliana, primary, Trigwell, Catherine, primary, Eberlein, Catherine, primary, Lenaghan, Carol, primary, Polanski, Radoslaw, primary, Avivar-Valderas, Alvaro, primary, Cumberbatch, Marie, primary, Klinowska, Teresa, primary, Critchlow, Susan E., primary, Cruzalegui, Francisco, primary, and Barry, Simon T., primary

Published
2023
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19. Supplementary Methods from Combined Inhibition of PI3Kβ and mTOR Inhibits Growth of PTEN-null Tumors

Author

Lynch, James T., primary, Polanska, Urszula M., primary, Hancox, Ursula, primary, Delpuech, Oona, primary, Maynard, Juliana, primary, Trigwell, Catherine, primary, Eberlein, Catherine, primary, Lenaghan, Carol, primary, Polanski, Radoslaw, primary, Avivar-Valderas, Alvaro, primary, Cumberbatch, Marie, primary, Klinowska, Teresa, primary, Critchlow, Susan E., primary, Cruzalegui, Francisco, primary, and Barry, Simon T., primary

Published
2023
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20. Supplementary Figures 1-5 from Combined Inhibition of PI3Kβ and mTOR Inhibits Growth of PTEN-null Tumors

Author

Lynch, James T., primary, Polanska, Urszula M., primary, Hancox, Ursula, primary, Delpuech, Oona, primary, Maynard, Juliana, primary, Trigwell, Catherine, primary, Eberlein, Catherine, primary, Lenaghan, Carol, primary, Polanski, Radoslaw, primary, Avivar-Valderas, Alvaro, primary, Cumberbatch, Marie, primary, Klinowska, Teresa, primary, Critchlow, Susan E., primary, Cruzalegui, Francisco, primary, and Barry, Simon T., primary

Published
2023
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21. Supplementary Table Results from Inhibiting PI3Kβ with AZD8186 Regulates Key Metabolic Pathways in PTEN-Null Tumors

Author

Lynch, James T., primary, Polanska, Urszula M., primary, Delpuech, Oona, primary, Hancox, Urs, primary, Trinidad, Antonio G., primary, Michopoulos, Filippos, primary, Lenaghan, Carol, primary, McEwen, Robert, primary, Bradford, James, primary, Polanski, Radek, primary, Ellston, Rebecca, primary, Avivar-Valderas, Alvaro, primary, Pilling, James, primary, Staniszewska, Anna, primary, Cumberbatch, Marie, primary, Critchlow, Susan E., primary, Cruzalegui, Francisco, primary, and Barry, Simon T., primary

Published
2023
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22. Supplementary Figures 1-9 from Inhibiting PI3Kβ with AZD8186 Regulates Key Metabolic Pathways in PTEN-Null Tumors

Author

Lynch, James T., primary, Polanska, Urszula M., primary, Delpuech, Oona, primary, Hancox, Urs, primary, Trinidad, Antonio G., primary, Michopoulos, Filippos, primary, Lenaghan, Carol, primary, McEwen, Robert, primary, Bradford, James, primary, Polanski, Radek, primary, Ellston, Rebecca, primary, Avivar-Valderas, Alvaro, primary, Pilling, James, primary, Staniszewska, Anna, primary, Cumberbatch, Marie, primary, Critchlow, Susan E., primary, Cruzalegui, Francisco, primary, and Barry, Simon T., primary

Published
2023
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23. Supplemental data figure legends from Inhibiting PI3Kβ with AZD8186 Regulates Key Metabolic Pathways in PTEN-Null Tumors

Author

Lynch, James T., primary, Polanska, Urszula M., primary, Delpuech, Oona, primary, Hancox, Urs, primary, Trinidad, Antonio G., primary, Michopoulos, Filippos, primary, Lenaghan, Carol, primary, McEwen, Robert, primary, Bradford, James, primary, Polanski, Radek, primary, Ellston, Rebecca, primary, Avivar-Valderas, Alvaro, primary, Pilling, James, primary, Staniszewska, Anna, primary, Cumberbatch, Marie, primary, Critchlow, Susan E., primary, Cruzalegui, Francisco, primary, and Barry, Simon T., primary

Published
2023
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24. Supplementary Table Methods from Inhibiting PI3Kβ with AZD8186 Regulates Key Metabolic Pathways in PTEN-Null Tumors

Author

Lynch, James T., primary, Polanska, Urszula M., primary, Delpuech, Oona, primary, Hancox, Urs, primary, Trinidad, Antonio G., primary, Michopoulos, Filippos, primary, Lenaghan, Carol, primary, McEwen, Robert, primary, Bradford, James, primary, Polanski, Radek, primary, Ellston, Rebecca, primary, Avivar-Valderas, Alvaro, primary, Pilling, James, primary, Staniszewska, Anna, primary, Cumberbatch, Marie, primary, Critchlow, Susan E., primary, Cruzalegui, Francisco, primary, and Barry, Simon T., primary

Published
2023
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34. mTOR inhibition amplifies the anti-lymphoma effect of PI3Kβ/δ blockage in diffuse large B-cell lymphoma

Author

Xu, Wendan, primary, Berning, Philipp, additional, Erdmann, Tabea, additional, Grau, Michael, additional, Bettazová, Nardjas, additional, Zapukhlyak, Myroslav, additional, Frontzek, Fabian, additional, Kosnopfel, Corinna, additional, Lenz, Peter, additional, Grondine, Michael, additional, Willis, Brandon, additional, Lynch, James T., additional, Klener, Pavel, additional, Hailfinger, Stephan, additional, Barry, Simon T., additional, and Lenz, Georg, additional

Published
2022
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37. Fragment-Based Design of a Potent MAT2a Inhibitor and in Vivo Evaluation in an MTAP Null Xenograft Model

Author

De Fusco, Claudia, primary, Schimpl, Marianne, additional, Börjesson, Ulf, additional, Cheung, Tony, additional, Collie, Iain, additional, Evans, Laura, additional, Narasimhan, Priyanka, additional, Stubbs, Christopher, additional, Vazquez-Chantada, Mercedes, additional, Wagner, David J., additional, Grondine, Michael, additional, Sanders, Matthew G., additional, Tentarelli, Sharon, additional, Underwood, Elizabeth, additional, Argyrou, Argyrides, additional, Smith, James M., additional, Lynch, James T., additional, Chiarparin, Elisabetta, additional, Robb, Graeme, additional, Bagal, Sharan K., additional, and Scott, James S., additional

Published
2021
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38. Enhancer Activation by Pharmacologic Displacement of LSD1 from GFI1 Induces Differentiation in Acute Myeloid Leukemia

Author

Maiques-Diaz, Alba, Spencer, Gary J., Lynch, James T., Ciceri, Filippo, Williams, Emma L., Amaral, Fabio M.R., Wiseman, Daniel H., Harris, William J., Li, Yaoyong, Sahoo, Sudhakar, Hitchin, James R., Mould, Daniel P., Fairweather, Emma E., Waszkowycz, Bohdan, Jordan, Allan M., Smith, Duncan L., and Somervaille, Tim C.P.

Subjects
MLL, Histone Demethylases, animal structures, GFI1, LSD1, Cell Differentiation, acute myeloid leukemia, Article, DNA-Binding Proteins, Leukemia, Myeloid, Acute, lcsh:Biology (General), hemic and lymphatic diseases, Humans, methylation, lcsh:QH301-705.5, acetylation, Transcription Factors
Abstract

Summary Pharmacologic inhibition of LSD1 promotes blast cell differentiation in acute myeloid leukemia (AML) with MLL translocations. The assumption has been that differentiation is induced through blockade of LSD1’s histone demethylase activity. However, we observed that rapid, extensive, drug-induced changes in transcription occurred without genome-wide accumulation of the histone modifications targeted for demethylation by LSD1 at sites of LSD1 binding and that a demethylase-defective mutant rescued LSD1 knockdown AML cells as efficiently as wild-type protein. Rather, LSD1 inhibitors disrupt the interaction of LSD1 and RCOR1 with the SNAG-domain transcription repressor GFI1, which is bound to a discrete set of enhancers located close to transcription factor genes that regulate myeloid differentiation. Physical separation of LSD1/RCOR1 from GFI1 is required for drug-induced differentiation. The consequent inactivation of GFI1 leads to increased enhancer histone acetylation within hours, which directly correlates with the upregulation of nearby subordinate genes., Graphical Abstract, Highlights • Inhibitors of LSD1 target both scaffolding and enzymatic functions of the protein • GFI1/CoREST complex is targeted for disruption and release from chromatin • GFI1/CoREST disruption is required for leukemia cell differentiation • Loss of enhancer-bound GFI1/LSD1 activates nearby myeloid differentiation genes, Maiques-Diaz et al. report that, while LSD1 inhibitors target both scaffolding and enzymatic functions of the protein, drug-induced myeloid leukemia cell differentiation is primarily due to the disruption and release from enhancers of GFI1/CoREST complexes, leading to the activation of subordinate myeloid transcription factor genes.

Published
2018

39. Natural killer--like T-cell lymphoma of the parotid in a patient infected with human immunodeficiency virus

Author

Cornfield, Dennis B., Papiez, Joseph S., Lynch, James T., and Rimsza, Lisa M.

Subjects
Lymphomas -- Case studies -- Complications and side effects, AIDS (Disease) -- Complications and side effects -- Case studies, Health
Abstract

* A 42-year-old man with acquired immunodeficiency syndrome developed a mass of the right parotid gland and multiple hepatic masses. Hematoxylin-eosin--stained sections of the parotid lesion showed a diffuse infiltrate of large mononuclear cells with vesicular nuclei and prominent nucleoli, consistent with a non-Hodgkin lymphoma. Immunohistochemical stains demonstrated expression of the T-cell markers CD3 and UCHL-1, as well as latent membrane protein 1 and T-cell intracellular antigen 1. Flow cytometry showed surface expression of CD2, CD3, CD7 (dim), CD8, and CD56. CD5 was not expressed. Molecular evaluation by polymerase chain reaction demonstrated monoclonal rearrangement of the T-cell receptor γ gene. Epstein-Barr virus early RNA and human immunodeficiency virus RNA were demonstrated by in situ hybridization. To our knowledge, this is the first reported case of T-cell lymphoma of the parotid in a patient infected with human immunodeficiency virus. After 2 separate chemotherapy regimens, the patient achieved clinical remission for 1 1/2 years; he then developed progressive pulmonary lesions and died., The high incidence of B-cell lymphoproliferative disorders in individuals infected with human immunodeficiency virus (HIV) became well known shortly after acquired immunodeficiency syndrome (AIDS) was first described in the 1980s. [...]

Published
2002

40. Drug mechanism‐of‐action discovery through the integration of pharmacological and CRISPR screens

Author

Gonçalves, Emanuel, primary, Segura‐Cabrera, Aldo, additional, Pacini, Clare, additional, Picco, Gabriele, additional, Behan, Fiona M, additional, Jaaks, Patricia, additional, Coker, Elizabeth A, additional, van der Meer, Donny, additional, Barthorpe, Andrew, additional, Lightfoot, Howard, additional, Mironenko, Tatiana, additional, Beck, Alexandra, additional, Richardson, Laura, additional, Yang, Wanjuan, additional, Lleshi, Ermira, additional, Hall, James, additional, Tolley, Charlotte, additional, Hall, Caitlin, additional, Mali, Iman, additional, Thomas, Frances, additional, Morris, James, additional, Leach, Andrew R, additional, Lynch, James T, additional, Sidders, Ben, additional, Crafter, Claire, additional, Iorio, Francesco, additional, Fawell, Stephen, additional, and Garnett, Mathew J, additional

Published
2020
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43. Abstract 321: Genome-wide CRISPR screens identify combination strategies for Capivasertib (AZD5363; AKT) and AZD8186 (PI3Kβ/δ) in PTEN-null breast cancer

Author

Dunn, Shanade, primary, Yu, Jason, additional, Gris-Oliver, Albert, additional, Pilling, James, additional, Hopcroft, Philip, additional, Yelland, Urs, additional, Cureton, Natalie, additional, Staniszewsla, Anna, additional, Au, Yan Zi, additional, Ong, Swee Hoe, additional, Isherwood, Beverley, additional, Serra, Violeta, additional, Barry, Simon, additional, Davies, Barry R., additional, Lynch, James T., additional, and Yusa, Kosuke, additional

Published
2019
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44. Combined Inhibition of PI3Kβ and mTOR Inhibits Growth of PTEN-null Tumors

Author

Lynch, James T., primary, Polanska, Urszula M., additional, Hancox, Ursula, additional, Delpuech, Oona, additional, Maynard, Juliana, additional, Trigwell, Catherine, additional, Eberlein, Catherine, additional, Lenaghan, Carol, additional, Polanski, Radoslaw, additional, Avivar-Valderas, Alvaro, additional, Cumberbatch, Marie, additional, Klinowska, Teresa, additional, Critchlow, Susan E., additional, Cruzalegui, Francisco, additional, and Barry, Simon T., additional

Published
2018
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45. The role of glucocorticoid receptor phosphorylation in Mcl-1 and NOXA gene expression

Author

Demonacos Constantinos, Berrou Ilhem, Xenaki Georgia, Rajendran Ramkumar, Lynch James T, and Krstic-Demonacos Marija

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background The cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) mediated phosphorylation of glucocorticoid receptor (GR) exerts opposite effects on GR transcriptional activity and affects other posttranslational modifications within this protein. The major phosphorylation site of human GR targeted by MAPK family is the serine 226 and multiple kinase complexes phosphorylate receptor at the serine 211 residue. We hypothesize that GR posttranslational modifications are involved in the determination of the cellular fate in human lymphoblastic leukemia cells. We investigated whether UV signalling through alternative GR phosphorylation determined the cell type specificity of glucocorticoids (GCs) mediated apoptosis. Results We have identified putative Glucocorticoid Response Elements (GREs) within the promoter regulatory regions of the Bcl-2 family members NOXA and Mcl-1 indicating that they are direct GR transcriptional targets. These genes were differentially regulated in CEM-C7-14, CEM-C1-15 and A549 cells by glucocorticoids and JNK pathway. In addition, our results revealed that the S211 phosphorylation was dominant in CEM-C7-14, whereas the opposite was the case in CEM-C1-15 where prevalence of S226 GR phosphorylation was observed. Furthermore, multiple GR isoforms with cell line specific patterns were identified in CEM-C7-14 cells compared to CEM-C1-15 and A549 cell lines with the same antibodies. Conclusions GR phosphorylation status kinetics, and site specificity as well as isoform variability differ in CEM-C7-14, CEM-C1-15, and A549 cells. The positive or negative response to GCs induced apoptosis in these cell lines is a consequence of the variable equilibrium of NOXA and Mcl-1 gene expression potentially mediated by alternatively phosphorylated GR, as well as the balance of MAPK/CDK pathways controlling GR phosphorylation pattern. Our results provide molecular base and valuable knowledge for improving the GC based therapies of leukaemia.

Published
2010
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46. Fragment-Based Design of a Potent MAT2a Inhibitor and in VivoEvaluation in an MTAP Null Xenograft Model

Author

De Fusco, Claudia, Schimpl, Marianne, Börjesson, Ulf, Cheung, Tony, Collie, Iain, Evans, Laura, Narasimhan, Priyanka, Stubbs, Christopher, Vazquez-Chantada, Mercedes, Wagner, David J., Grondine, Michael, Sanders, Matthew G., Tentarelli, Sharon, Underwood, Elizabeth, Argyrou, Argyrides, Smith, James M., Lynch, James T., Chiarparin, Elisabetta, Robb, Graeme, Bagal, Sharan K., and Scott, James S.

Abstract

MAT2a is a methionine adenosyltransferase that synthesizes the essential metabolite S-adenosylmethionine (SAM) from methionine and ATP. Tumors bearing the co-deletion of p16 and MTAP genes have been shown to be sensitive to MAT2a inhibition, making it an attractive target for treatment of MTAP-deleted cancers. A fragment-based lead generation campaign identified weak but efficient hits binding in a known allosteric site. By use of structure-guided design and systematic SAR exploration, the hits were elaborated through a merging and growing strategy into an arylquinazolinone series of potent MAT2a inhibitors. The selected in vivotool compound 28reduced SAM-dependent methylation events in cells and inhibited proliferation of MTAP-null cells in vitro. In vivostudies showed that 28was able to induce antitumor response in an MTAP knockout HCT116 xenograft model.

Published
2021
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48. Inhibiting PI3Kβ with AZD8186 Regulates Key Metabolic Pathways in PTEN-Null Tumors

Author

Lynch, James T., primary, Polanska, Urszula M., additional, Delpuech, Oona, additional, Hancox, Urs, additional, Trinidad, Antonio G., additional, Michopoulos, Filippos, additional, Lenaghan, Carol, additional, McEwen, Robert, additional, Bradford, James, additional, Polanski, Radek, additional, Ellston, Rebecca, additional, Avivar-Valderas, Alvaro, additional, Pilling, James, additional, Staniszewska, Anna, additional, Cumberbatch, Marie, additional, Critchlow, Susan E., additional, Cruzalegui, Francisco, additional, and Barry, Simon T., additional

Published
2017
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50. Discovery and In VivoEfficacy of AZ-PRMT5i-1, a Novel PRMT5 Inhibitor with High MTA Cooperativity

Author

Smith, James M., Barlaam, Bernard, Beattie, David, Bradshaw, Lauren, Chan, Ho Man, Chiarparin, Elisabetta, Collingwood, Olga, Cooke, Sophie L., Cronin, Anna, Cumming, Iain, Dean, Emma, Debreczeni, Judit É., del Barco Barrantes, Iván, Diene, Coura, Gianni, Davide, Guerot, Carine, Guo, Xiaoxiao, Guven, Sinem, Hayhow, Thomas G., Hong, Ted, Kemmitt, Paul D., Lamont, Gillian M., Lamont, Scott, Lynch, James T., McWilliams, Lisa, Moore, Shaun, Raubo, Piotr, Robb, Graeme R., Robinson, James, Scott, James S., Srinivasan, Bharath, Steward, Oliver, Stubbs, Christopher J., Syson, Karl, Tan, Lixiang, Turner, Oliver, Underwood, Elizabeth, Urosevic, Jelena, Vazquez-Chantada, Mercedes, Whittaker, Amy L., Wilson, David M., and Winter-Holt, Jon J.

Abstract

PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in cancer. With the aim of developing MTA-cooperative PRMT5 inhibitors suitable for MTAP-deficient cancers, herein we report our efforts to develop novel “MTA-cooperative” compounds identified through a high-throughput biochemical screening approach. Optimization of hits was achieved through structure-based design with a focus on improvement of oral drug-like properties. Bioisosteric replacement of the original thiazole guanidine headgroup, spirocyclization of the isoindolinone amide scaffold to both configurationally and conformationally lock the bioactive form, and fine-tuning of the potency, MTA cooperativity, and DMPK properties through specific substitutions of the azaindole headgroup were conducted. We have identified an orally available in vivolead compound, 28(“AZ-PRMT5i-1”), which shows sub-10 nM PRMT5 cell potency, >50-fold MTA cooperativity, suitable DMPK properties for oral dosing, and significant PRMT5-driven in vivoefficacy in several MTAP-deficient preclinical cancer models.

Published
2024
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