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2. Unbound Brain-to-Plasma Partition Coefficient, Kp,uu,brain—a Game Changing Parameter for CNS Drug Discovery and Development

Author

Loryan, Irena, Reichel, Andreas, Feng, Bo, Bundgaard, Christoffer, Shaffer, Christopher, Kalvass, Cory, Bednarczyk, Dallas, Morrison, Denise, Lesuisse, Dominique, Hoppe, Edmund, Terstappen, Georg C., Fischer, Holger, Di, Li, Colclough, Nicola, Summerfield, Scott, Buckley, Stephen T., Maurer, Tristan S., and Fridén, Markus

Published
2022
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3. Highly Optimized CNS Penetrant Inhibitors of EGFR Exon20 Insertion Mutations.

Author

McCoull, William, Thomson, Clare, Braybrooke, Erin, Chan, Christina, Colclough, Nicola, Cortés González, Miguel A., Cosulich, Sabina, Davies, Nichola L., Floc'h, Nicolas, Greenwood, Ryan, Hargreaves, David, Huang, Peng, Hunt, Thomas A., Johnson, Tony, Johnström, Peter, Kettle, Jason G., Kondrashov, Mikhail, Kostomiris, Demetrios H., Li, Songlei, and Lister, Andrew

Published
2025
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4. Brain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in EGFR-mutant lung cancer

Author

Adua, Sally J., Arnal-Estapé, Anna, Zhao, Minghui, Qi, Bowen, Liu, Zongzhi Z., Kravitz, Carolyn, Hulme, Heather, Strittmatter, Nicole, López-Giráldez, Francesc, Chande, Sampada, Albert, Alexandra E., Melnick, Mary-Ann, Hu, Bomiao, Politi, Katerina, Chiang, Veronica, Colclough, Nicola, Goodwin, Richard J. A., Cross, Darren, Smith, Paul, and Nguyen, Don X.

Published
2022
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5. Optimization of Potent, Efficacious, Selective and Blood–Brain Barrier Penetrating Inhibitors Targeting EGFR Exon20 Insertion Mutations.

Author

Thomson, Clare, Braybrooke, Erin, Colclough, Nicola, Davies, Nichola L., Floc'h, Nicolas, Greenwood, Ryan, Guérot, Carine, Hargreaves, David, Johnstrom, Peter, Khurana, Puneet, Kostomiris, Demetrios H., Li, Songlei, Lister, Andrew, Lorthioir, Olivier, Martin, Scott, McCoull, William, McLean, Neville J., McWilliams, Lisa, Orme, Jonathan P., and Packer, Martin J.

Published
2024
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7. Identification of Novel, Selective Ataxia-Telangiectasia Mutated Kinase Inhibitors with the Ability to Penetrate the Blood–Brain Barrier: The Discovery of AZD1390

Author

Pike, Kurt G., primary, Hunt, Thomas A., additional, Barlaam, Bernard, additional, Benstead, David, additional, Cadogan, Elaine, additional, Chen, Kan, additional, Cook, Calum R., additional, Colclough, Nicola, additional, Deng, Chao, additional, Durant, Stephen T., additional, Eatherton, Andrew, additional, Goldberg, Kristin, additional, Johnström, Peter, additional, Liu, Libin, additional, Liu, Zhaoqun, additional, Nissink, J. Willem M., additional, Pang, Chengling, additional, Pass, Martin, additional, Robb, Graeme R., additional, Roberts, Caroline, additional, Schou, Magnus, additional, Steward, Oliver, additional, Sykes, Andy, additional, Yan, Yumei, additional, Zhai, Baochang, additional, and Zheng, Li, additional

Published
2024
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9. Utilising a dual human transporter MDCKII-MDR1-BCRP cell line to assess efflux at the Blood Brain Barrier (BBB)

Author

Colclough, Nicola, primary, Alluri, Ravindra V, additional, Tucker, James W, additional, Gozalpour, Elnaz, additional, Li, Danxi, additional, Du, Hongwen, additional, Li, Wei, additional, Harlfinger, Stephanie, additional, O'Neill, Daniel J., additional, Sproat, Graham G., additional, Chen, Kan, additional, Yan, Yumei, additional, and McGinnity, Dermot F, additional

Published
2023
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11. Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations.

Author

Thomson, Clare, Barton, Peter, Braybrooke, Erin, Colclough, Nicola, Dong, Zhiqiang, Evans, Laura, Floc'h, Nicolas, Guérot, Carine, Hargreaves, David, Khurana, Puneet, Li, Songlei, Li, Xiuwei, Lister, Andrew, McCoull, William, McWilliams, Lisa, Orme, Jonathan P., Packer, Martin J., Swaih, Aisha M., Ward, Richard A., and Winlow, Poppy

Published
2024
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13. Video 1 - ATMi increases the rate of mitotic catastrophe in glioma cells when p53 is knocked down. from Orally Bioavailable and Blood–Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice

Author

Karlin, Jeremy, primary, Allen, Jasmine, primary, Ahmad, Syed F., primary, Hughes, Gareth, primary, Sheridan, Victoria, primary, Odedra, Rajesh, primary, Farrington, Paul, primary, Cadogan, Elaine B., primary, Riches, Lucy C., primary, Garcia-Trinidad, Antonio, primary, Thomason, Andrew G., primary, Patel, Bhavika, primary, Vincent, Jennifer, primary, Lau, Alan, primary, Pike, Kurt G., primary, Hunt, Thomas A., primary, Sule, Amrita, primary, Valerie, Nicholas C.K., primary, Biddlestone-Thorpe, Laura, primary, Kahn, Jenna, primary, Beckta, Jason M., primary, Mukhopadhyay, Nitai, primary, Barlaam, Bernard, primary, Degorce, Sebastien L., primary, Kettle, Jason, primary, Colclough, Nicola, primary, Wilson, Joanne, primary, Smith, Aaron, primary, Barrett, Ian P., primary, Zheng, Li, primary, Zhang, Tianwei, primary, Wang, Yingchun, primary, Chen, Kan, primary, Pass, Martin, primary, Durant, Stephen T., primary, and Valerie, Kristoffer, primary

Published
2023
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14. Video 4 - ATMi increases the rate of mitotic catastrophe in glioma cells when p53 is knocked down. from Orally Bioavailable and Blood–Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice

Author

Karlin, Jeremy, primary, Allen, Jasmine, primary, Ahmad, Syed F., primary, Hughes, Gareth, primary, Sheridan, Victoria, primary, Odedra, Rajesh, primary, Farrington, Paul, primary, Cadogan, Elaine B., primary, Riches, Lucy C., primary, Garcia-Trinidad, Antonio, primary, Thomason, Andrew G., primary, Patel, Bhavika, primary, Vincent, Jennifer, primary, Lau, Alan, primary, Pike, Kurt G., primary, Hunt, Thomas A., primary, Sule, Amrita, primary, Valerie, Nicholas C.K., primary, Biddlestone-Thorpe, Laura, primary, Kahn, Jenna, primary, Beckta, Jason M., primary, Mukhopadhyay, Nitai, primary, Barlaam, Bernard, primary, Degorce, Sebastien L., primary, Kettle, Jason, primary, Colclough, Nicola, primary, Wilson, Joanne, primary, Smith, Aaron, primary, Barrett, Ian P., primary, Zheng, Li, primary, Zhang, Tianwei, primary, Wang, Yingchun, primary, Chen, Kan, primary, Pass, Martin, primary, Durant, Stephen T., primary, and Valerie, Kristoffer, primary

Published
2023
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15. Data from Orally Bioavailable and Blood–Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice

Author

Karlin, Jeremy, primary, Allen, Jasmine, primary, Ahmad, Syed F., primary, Hughes, Gareth, primary, Sheridan, Victoria, primary, Odedra, Rajesh, primary, Farrington, Paul, primary, Cadogan, Elaine B., primary, Riches, Lucy C., primary, Garcia-Trinidad, Antonio, primary, Thomason, Andrew G., primary, Patel, Bhavika, primary, Vincent, Jennifer, primary, Lau, Alan, primary, Pike, Kurt G., primary, Hunt, Thomas A., primary, Sule, Amrita, primary, Valerie, Nicholas C.K., primary, Biddlestone-Thorpe, Laura, primary, Kahn, Jenna, primary, Beckta, Jason M., primary, Mukhopadhyay, Nitai, primary, Barlaam, Bernard, primary, Degorce, Sebastien L., primary, Kettle, Jason, primary, Colclough, Nicola, primary, Wilson, Joanne, primary, Smith, Aaron, primary, Barrett, Ian P., primary, Zheng, Li, primary, Zhang, Tianwei, primary, Wang, Yingchun, primary, Chen, Kan, primary, Pass, Martin, primary, Durant, Stephen T., primary, and Valerie, Kristoffer, primary

Published
2023
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16. Supplementary Information from Orally Bioavailable and Blood–Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice

Author

Karlin, Jeremy, primary, Allen, Jasmine, primary, Ahmad, Syed F., primary, Hughes, Gareth, primary, Sheridan, Victoria, primary, Odedra, Rajesh, primary, Farrington, Paul, primary, Cadogan, Elaine B., primary, Riches, Lucy C., primary, Garcia-Trinidad, Antonio, primary, Thomason, Andrew G., primary, Patel, Bhavika, primary, Vincent, Jennifer, primary, Lau, Alan, primary, Pike, Kurt G., primary, Hunt, Thomas A., primary, Sule, Amrita, primary, Valerie, Nicholas C.K., primary, Biddlestone-Thorpe, Laura, primary, Kahn, Jenna, primary, Beckta, Jason M., primary, Mukhopadhyay, Nitai, primary, Barlaam, Bernard, primary, Degorce, Sebastien L., primary, Kettle, Jason, primary, Colclough, Nicola, primary, Wilson, Joanne, primary, Smith, Aaron, primary, Barrett, Ian P., primary, Zheng, Li, primary, Zhang, Tianwei, primary, Wang, Yingchun, primary, Chen, Kan, primary, Pass, Martin, primary, Durant, Stephen T., primary, and Valerie, Kristoffer, primary

Published
2023
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17. Video 2 - ATMi increases the rate of mitotic catastrophe in glioma cells when p53 is knocked down. from Orally Bioavailable and Blood–Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice

Author

Karlin, Jeremy, primary, Allen, Jasmine, primary, Ahmad, Syed F., primary, Hughes, Gareth, primary, Sheridan, Victoria, primary, Odedra, Rajesh, primary, Farrington, Paul, primary, Cadogan, Elaine B., primary, Riches, Lucy C., primary, Garcia-Trinidad, Antonio, primary, Thomason, Andrew G., primary, Patel, Bhavika, primary, Vincent, Jennifer, primary, Lau, Alan, primary, Pike, Kurt G., primary, Hunt, Thomas A., primary, Sule, Amrita, primary, Valerie, Nicholas C.K., primary, Biddlestone-Thorpe, Laura, primary, Kahn, Jenna, primary, Beckta, Jason M., primary, Mukhopadhyay, Nitai, primary, Barlaam, Bernard, primary, Degorce, Sebastien L., primary, Kettle, Jason, primary, Colclough, Nicola, primary, Wilson, Joanne, primary, Smith, Aaron, primary, Barrett, Ian P., primary, Zheng, Li, primary, Zhang, Tianwei, primary, Wang, Yingchun, primary, Chen, Kan, primary, Pass, Martin, primary, Durant, Stephen T., primary, and Valerie, Kristoffer, primary

Published
2023
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18. Video 3 - ATMi increases the rate of mitotic catastrophe in glioma cells when p53 is knocked down. from Orally Bioavailable and Blood–Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice

Author

Karlin, Jeremy, primary, Allen, Jasmine, primary, Ahmad, Syed F., primary, Hughes, Gareth, primary, Sheridan, Victoria, primary, Odedra, Rajesh, primary, Farrington, Paul, primary, Cadogan, Elaine B., primary, Riches, Lucy C., primary, Garcia-Trinidad, Antonio, primary, Thomason, Andrew G., primary, Patel, Bhavika, primary, Vincent, Jennifer, primary, Lau, Alan, primary, Pike, Kurt G., primary, Hunt, Thomas A., primary, Sule, Amrita, primary, Valerie, Nicholas C.K., primary, Biddlestone-Thorpe, Laura, primary, Kahn, Jenna, primary, Beckta, Jason M., primary, Mukhopadhyay, Nitai, primary, Barlaam, Bernard, primary, Degorce, Sebastien L., primary, Kettle, Jason, primary, Colclough, Nicola, primary, Wilson, Joanne, primary, Smith, Aaron, primary, Barrett, Ian P., primary, Zheng, Li, primary, Zhang, Tianwei, primary, Wang, Yingchun, primary, Chen, Kan, primary, Pass, Martin, primary, Durant, Stephen T., primary, and Valerie, Kristoffer, primary

Published
2023
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20. Supplementary Data from Preclinical Comparison of the Blood–brain barrier Permeability of Osimertinib with Other EGFR TKIs

Author

Colclough, Nicola, primary, Chen, Kan, primary, Johnström, Peter, primary, Strittmatter, Nicole, primary, Yan, Yumei, primary, Wrigley, Gail L., primary, Schou, Magnus, primary, Goodwin, Richard, primary, Varnäs, Katarina, primary, Adua, Sally J., primary, Zhao, Minghui, primary, Nguyen, Don X., primary, Maglennon, Gareth, primary, Barton, Peter, primary, Atkinson, James, primary, Zhang, Lin, primary, Janefeldt, Annika, primary, Wilson, Joanne, primary, Smith, Aaron, primary, Takano, Akihiro, primary, Arakawa, Ryosuke, primary, Kondrashov, Mikhail, primary, Malmquist, Jonas, primary, Revunov, Evgeny, primary, Vazquez-Romero, Ana, primary, Moein, Mohammad Mahdi, primary, Windhorst, Albert D., primary, Karp, Natasha A., primary, Finlay, M. Raymond V., primary, Ward, Richard A., primary, Yates, James W.T., primary, Smith, Paul D., primary, Farde, Lars, primary, Cheng, Zack, primary, and Cross, Darren A.E., primary

Published
2023
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21. Figure S1 from Preclinical Comparison of the Blood–brain barrier Permeability of Osimertinib with Other EGFR TKIs

Author

Colclough, Nicola, primary, Chen, Kan, primary, Johnström, Peter, primary, Strittmatter, Nicole, primary, Yan, Yumei, primary, Wrigley, Gail L., primary, Schou, Magnus, primary, Goodwin, Richard, primary, Varnäs, Katarina, primary, Adua, Sally J., primary, Zhao, Minghui, primary, Nguyen, Don X., primary, Maglennon, Gareth, primary, Barton, Peter, primary, Atkinson, James, primary, Zhang, Lin, primary, Janefeldt, Annika, primary, Wilson, Joanne, primary, Smith, Aaron, primary, Takano, Akihiro, primary, Arakawa, Ryosuke, primary, Kondrashov, Mikhail, primary, Malmquist, Jonas, primary, Revunov, Evgeny, primary, Vazquez-Romero, Ana, primary, Moein, Mohammad Mahdi, primary, Windhorst, Albert D., primary, Karp, Natasha A., primary, Finlay, M. Raymond V., primary, Ward, Richard A., primary, Yates, James W.T., primary, Smith, Paul D., primary, Farde, Lars, primary, Cheng, Zack, primary, and Cross, Darren A.E., primary

Published
2023
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23. Unbound Brain-to-Plasma Partition Coefficient, K-p,K-uu,K-brain-a Game Changing Parameter for CNS Drug Discovery and Development

Author

Loryan, Irena, Reichel, Andreas, Feng, Bo, Bundgaard, Christoffer, Shaffer, Christopher, Kalvass, Cory, Bednarczyk, Dallas, Morrison, Denise, Lesuisse, Dominique, Hoppe, Edmund, Terstappen, Georg C., Fischer, Holger, Di, Li, Colclough, Nicola, Summerfield, Scott, Buckley, Stephen T., Maurer, Tristan S., Fridén, Markus, Loryan, Irena, Reichel, Andreas, Feng, Bo, Bundgaard, Christoffer, Shaffer, Christopher, Kalvass, Cory, Bednarczyk, Dallas, Morrison, Denise, Lesuisse, Dominique, Hoppe, Edmund, Terstappen, Georg C., Fischer, Holger, Di, Li, Colclough, Nicola, Summerfield, Scott, Buckley, Stephen T., Maurer, Tristan S., and Fridén, Markus

Abstract

Purpose More than 15 years have passed since the first description of the unbound brain-to-plasma partition coefficient (K-p,K-uu,K-brain) by Prof. Margareta Hammarlund-Udenaes, which was enabled by advancements in experimental methodologies including cerebral microdialysis. Since then, growing knowledge and data continue to support the notion that the unbound (free) concentration of a drug at the site of action, such as the brain, is the driving force for pharmacological responses. Towards this end, K-p,K-uu,K-brain is the key parameter to obtain unbound brain concentrations from unbound plasma concentrations. Methods To understand the importance and impact of the K-p,K-uu,K-brain concept in contemporary drug discovery and development, a survey has been conducted amongst major pharmaceutical companies based in Europe and the USA. Here, we present the results from this survey which consisted of 47 questions addressing: 1) Background information of the companies, 2) Implementation, 3) Application areas, 4) Methodology, 5) Impact and 6) Future perspectives. Results and conclusions From the responses, it is clear that the majority of the companies (93%) has established a common understanding across disciplines of the concept and utility of K-p,K-uu,K-brain as compared to other parameters related to brain exposure. Adoption of the K-p,K-uu,K-brain concept has been mainly driven by individual scientists advocating its application in the various companies rather than by a top-down approach. Remarkably, 79% of all responders describe the portfolio impact of K-p,K-uu,K-brain implementation in their companies as 'game-changing'. Although most companies (74%) consider the current toolbox for K-p,K-uu,K-brain assessment and its validation satisfactory for drug discovery and early development, areas of improvement and future research to better understand human brain pharmacokinetics/pharmacodynamics translation have been identified.

Published
2022
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29. Potent and Selective Inhibitors of the Epidermal Growth Factor Receptor to Overcome C797S-Mediated Resistance

Author

Finlay, M. Raymond V., primary, Barton, Peter, additional, Bickerton, Sue, additional, Bista, Michal, additional, Colclough, Nicola, additional, Cross, Darren A. E., additional, Evans, Laura, additional, Floc’h, Nicolas, additional, Gregson, Clare, additional, Guérot, Carine M., additional, Hargreaves, David, additional, Kang, Xiaoming, additional, Lenz, Eva M., additional, Li, Xu, additional, Liu, Yi, additional, Lorthioir, Olivier, additional, Martin, Matthew J., additional, McKerrecher, Darren, additional, McWhirter, Claire, additional, O’Neill, Daniel, additional, Orme, Jonathan P., additional, Mosallanejad, Arash, additional, Rahi, Amar, additional, Smith, Paul D., additional, Talbot, Verity, additional, Ward, Richard A., additional, Wrigley, Gail, additional, Wylot, Marta, additional, Xue, Lin, additional, Yao, Tieguang, additional, Ye, Yang, additional, and Zhao, Xiliang, additional

Published
2021
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31. Unbound Brain-to-Plasma Partition Coefficient, Kp,uu,brain—a Game Changing Parameter for CNS Drug Discovery and Development.

Author

Loryan, Irena, Reichel, Andreas, Feng, Bo, Bundgaard, Christoffer, Shaffer, Christopher, Kalvass, Cory, Bednarczyk, Dallas, Morrison, Denise, Lesuisse, Dominique, Hoppe, Edmund, Terstappen, Georg C., Fischer, Holger, Di, Li, Colclough, Nicola, Summerfield, Scott, Buckley, Stephen T., Maurer, Tristan S., and Fridén, Markus

Subjects
DRUG discovery, DRUG development, MICRODIALYSIS, PHARMACODYNAMICS, PHARMACOKINETICS
Abstract

Purpose: More than 15 years have passed since the first description of the unbound brain-to-plasma partition coefficient (Kp,uu,brain) by Prof. Margareta Hammarlund-Udenaes, which was enabled by advancements in experimental methodologies including cerebral microdialysis. Since then, growing knowledge and data continue to support the notion that the unbound (free) concentration of a drug at the site of action, such as the brain, is the driving force for pharmacological responses. Towards this end, Kp,uu,brain is the key parameter to obtain unbound brain concentrations from unbound plasma concentrations. Methods: To understand the importance and impact of the Kp,uu,brain concept in contemporary drug discovery and development, a survey has been conducted amongst major pharmaceutical companies based in Europe and the USA. Here, we present the results from this survey which consisted of 47 questions addressing: 1) Background information of the companies, 2) Implementation, 3) Application areas, 4) Methodology, 5) Impact and 6) Future perspectives. Results and conclusions: From the responses, it is clear that the majority of the companies (93%) has established a common understanding across disciplines of the concept and utility of Kp,uu,brain as compared to other parameters related to brain exposure. Adoption of the Kp,uu,brain concept has been mainly driven by individual scientists advocating its application in the various companies rather than by a top-down approach. Remarkably, 79% of all responders describe the portfolio impact of Kp,uu,brain implementation in their companies as 'game-changing'. Although most companies (74%) consider the current toolbox for Kp,uu,brain assessment and its validation satisfactory for drug discovery and early development, areas of improvement and future research to better understand human brain pharmacokinetics/pharmacodynamics translation have been identified. [ABSTRACT FROM AUTHOR]

Published
2022
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33. Preclinical Comparison of the Blood–brain barrier Permeability of Osimertinib with Other EGFR TKIs

Author

Colclough, Nicola, primary, Chen, Kan, additional, Johnström, Peter, additional, Strittmatter, Nicole, additional, Yan, Yumei, additional, Wrigley, Gail L., additional, Schou, Magnus, additional, Goodwin, Richard, additional, Varnäs, Katarina, additional, Adua, Sally J., additional, Zhao, Minghui, additional, Nguyen, Don X., additional, Maglennon, Gareth, additional, Barton, Peter, additional, Atkinson, James, additional, Zhang, Lin, additional, Janefeldt, Annika, additional, Wilson, Joanne, additional, Smith, Aaron, additional, Takano, Akihiro, additional, Arakawa, Ryosuke, additional, Kondrashov, Mikhail, additional, Malmquist, Jonas, additional, Revunov, Evgeny, additional, Vazquez-Romero, Ana, additional, Moein, Mohammad Mahdi, additional, Windhorst, Albert D., additional, Karp, Natasha A., additional, Finlay, M. Raymond V., additional, Ward, Richard A., additional, Yates, James W.T., additional, Smith, Paul D., additional, Farde, Lars, additional, Cheng, Zack, additional, and Cross, Darren A.E., additional

Published
2021
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36. Abstract 4813: Comparative activity profiling of tyrosine kinase inhibitors (TKIs) against exon 20 insertions and the wild-type form of epidermal growth factor receptor (EGFR)

Author

Ward, Richard A., primary, Bianco, Ambra, additional, Colclough, Nicola, additional, Cross, Darren, additional, Cuomo, Emanuela M., additional, Finlay, M. Raymond V., additional, Fitzek, Martina, additional, Floc’h, Nicolas, additional, Gagrica, Sladjana, additional, Hammond, Beverley, additional, Martin, Matthew J., additional, McKerrecher, Darren, additional, O’Neill, Daniel J., additional, Orme, Jonathan P., additional, Smith, Paul D., additional, Staniszewska, Anna D., additional, Urosevic, Jelena, additional, Whalley, Nicky, additional, and Yates, James W., additional

Published
2019
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37. Abstract 4868: A preclinical PK/PD model based on a mouse glioblastoma survival model for AZD1390, a novel, brain-penetrant ATM kinase inhibitor, to predict the inhibition of DNA damage response induced by radiation and the human efficacious dose

Author

Reddy, Venkatesh Pilla, primary, Sykes, Andy, additional, Colclough, Nicola, additional, Durant, Stephen T., additional, O'Connor, Lenka Oplustil, additional, Hoch, Matthias, additional, Bruna, Nuria Buil, additional, Vita, Serena De, additional, Merchant, Melinda, additional, and Pass, Martin, additional

Published
2019
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38. Abstract 4451: Evaluation of the therapeutic potential of phosphine oxide pyrazole inhibitors in tumors harboring EGFR C797S mutation

Author

Floch, Nicolas, primary, Finlay, M. Raymond V., additional, Bianco, Ambra, additional, Bickerton, Sue, additional, Colclough, Nicola, additional, Cross, Darren A., additional, Cuomo, Emanuela M., additional, Guerot, Carine M., additional, Hargreaves, David, additional, Martin, Matthew J., additional, McKerrecher, Darren, additional, O’Neill, Daniel J., additional, Orme, Jonathan P., additional, Rahi, Amar, additional, Smith, Paul D., additional, and Ward, Richard A., additional

Published
2019
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39. Utilizing microphysiological systems and induced pluripotent stem cells for disease modeling : a case study for blood brain barrier research in a pharmaceutical setting

Author

Fabre, Kristin M., Delsing, Louise, Hicks, Ryan, Colclough, Nicola, Crowther, Damian C., Ewart, Lorna, Fabre, Kristin M., Delsing, Louise, Hicks, Ryan, Colclough, Nicola, Crowther, Damian C., and Ewart, Lorna

Abstract

Microphysiological systems (MPS) may be able to provide the pharmaceutical industry models that can reflect human physiological responses to improve drug discovery and translational outcomes. With lack of efficacy being the primary cause for drug attrition, developing MPS disease models would help researchers identify novel targets, study mechanisms in more physiologically-relevant depth, screen for novel biomarkers and test/optimize various therapeutics (small molecules, nanoparticles and biologics). Furthermore, with advances in inducible pluripotent stem cell technology (iPSC), pharmaceutical companies can access cells from patients to help recreate specific disease phenotypes in MPS platforms. Combining iPSC and MPS technologies will contribute to our understanding of the complexities of neurodegenerative diseases and of the blood brain barrier (BBB) leading to development of enhanced therapeutics. © 2018

Published
2019
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41. Orally Bioavailable and Blood–Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice

Author

Karlin, Jeremy, primary, Allen, Jasmine, additional, Ahmad, Syed F., additional, Hughes, Gareth, additional, Sheridan, Victoria, additional, Odedra, Rajesh, additional, Farrington, Paul, additional, Cadogan, Elaine B., additional, Riches, Lucy C., additional, Garcia-Trinidad, Antonio, additional, Thomason, Andrew G., additional, Patel, Bhavika, additional, Vincent, Jennifer, additional, Lau, Alan, additional, Pike, Kurt G., additional, Hunt, Thomas A., additional, Sule, Amrita, additional, Valerie, Nicholas C.K., additional, Biddlestone-Thorpe, Laura, additional, Kahn, Jenna, additional, Beckta, Jason M., additional, Mukhopadhyay, Nitai, additional, Barlaam, Bernard, additional, Degorce, Sebastien L., additional, Kettle, Jason, additional, Colclough, Nicola, additional, Wilson, Joanne, additional, Smith, Aaron, additional, Barrett, Ian P., additional, Zheng, Li, additional, Zhang, Tianwei, additional, Wang, Yingchun, additional, Chen, Kan, additional, Pass, Martin, additional, Durant, Stephen T., additional, and Valerie, Kristoffer, additional

Published
2018
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42. Discovery of a Series of 3-Cinnoline Carboxamides as Orally Bioavailable, Highly Potent, and Selective ATM Inhibitors

Author

Barlaam, Bernard, primary, Cadogan, Elaine, additional, Campbell, Andrew, additional, Colclough, Nicola, additional, Dishington, Allan, additional, Durant, Stephen, additional, Goldberg, Kristin, additional, Hassall, Lorraine A., additional, Hughes, Gareth D., additional, MacFaul, Philip A., additional, McGuire, Thomas M., additional, Pass, Martin, additional, Patel, Anil, additional, Pearson, Stuart, additional, Petersen, Jens, additional, Pike, Kurt G., additional, Robb, Graeme, additional, Stratton, Natalie, additional, Xin, Guohong, additional, and Zhai, Baochang, additional

Published
2018
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43. The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models

Author

Durant, Stephen T., primary, Zheng, Li, additional, Wang, Yingchun, additional, Chen, Kan, additional, Zhang, Lingli, additional, Zhang, Tianwei, additional, Yang, Zhenfan, additional, Riches, Lucy, additional, Trinidad, Antonio G., additional, Fok, Jacqueline H. L., additional, Hunt, Tom, additional, Pike, Kurt G., additional, Wilson, Joanne, additional, Smith, Aaron, additional, Colclough, Nicola, additional, Reddy, Venkatesh Pilla, additional, Sykes, Andrew, additional, Janefeldt, Annika, additional, Johnström, Peter, additional, Varnäs, Katarina, additional, Takano, Akihiro, additional, Ling, Stephanie, additional, Orme, Jonathan, additional, Stott, Jonathan, additional, Roberts, Caroline, additional, Barrett, Ian, additional, Jones, Gemma, additional, Roudier, Martine, additional, Pierce, Andrew, additional, Allen, Jasmine, additional, Kahn, Jenna, additional, Sule, Amrita, additional, Karlin, Jeremy, additional, Cronin, Anna, additional, Chapman, Melissa, additional, Valerie, Kristoffer, additional, Illingworth, Ruth, additional, and Pass, Martin, additional

Published
2018
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44. The Identification of Potent, Selective, and Orally Available Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase: The Discovery of AZD0156 (8-{6-[3-(Dimethylamino)propoxy]pyridin-3-yl}-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one)

Author

Pike, Kurt G., primary, Barlaam, Bernard, additional, Cadogan, Elaine, additional, Campbell, Andrew, additional, Chen, Yingxue, additional, Colclough, Nicola, additional, Davies, Nichola L., additional, de-Almeida, Camila, additional, Degorce, Sebastien L., additional, Didelot, Myriam, additional, Dishington, Allan, additional, Ducray, Richard, additional, Durant, Stephen T., additional, Hassall, Lorraine A., additional, Holmes, Jane, additional, Hughes, Gareth D., additional, MacFaul, Philip A., additional, Mulholland, Keith R., additional, McGuire, Thomas M., additional, Ouvry, Gilles, additional, Pass, Martin, additional, Robb, Graeme, additional, Stratton, Natalie, additional, Wang, Zhenhua, additional, Wilson, Joanne, additional, Zhai, Baochang, additional, Zhao, Kang, additional, and Al-Huniti, Nidal, additional

Published
2018
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45. Abstract A104: AZD1390, a potent and selective orally bioavailable blood-brain barrier-penetrant ATM inhibitor, radiosensitizes and improves survival of orthotopic glioma and metastatic brain tumor models

Author

Durant, Steve T., primary, Pike, Kurt G., additional, Colclough, Nicola, additional, Riches, Lucy, additional, Garcia-Trinidad, Antonio, additional, Hunt, Thomas, additional, Ling, Stephanie, additional, Stott, Jonathan, additional, Barrett, Ian, additional, Zheng, Li, additional, Wang, Yingchun, additional, Chen, Kan, additional, Zhang, Tianwei, additional, Pilla Reddy, Venkatesh, additional, Sykes, Andrew, additional, Johnstrom, Peter, additional, Jones, Gemma, additional, Pierce, Andrew, additional, Karlin, Jeremy, additional, Kahn, Jenna, additional, Allen, Jasmine, additional, Valerie, Kristoffer, additional, Illingworth, Ruth, additional, and Pass, Martin, additional

Published
2018
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47. Abstract 2079: Osimertinib, an irreversible mutant selective EGFR tyrosine kinase inhibitor, exerts anti tumor activity in NSCLC harbouring exon 20 insertion mutant-EGFR

Author

Floc'h, Nicolas, primary, Ashton, Susan, additional, Bianco, Ambra, additional, Colclough, Nicola, additional, Cross, Darren AE, additional, Cuomo, Maria Emanuela, additional, Finlay, M. Raymond V., additional, Martin, Matthew J, additional, Menard, Ludovic, additional, McKerrecher, Darren, additional, O'Neill, Daniel J, additional, Orme, Jonathan P, additional, Staniszewska, Anna D, additional, Ward, Richard A, additional, and Yates, James W T, additional

Published
2017
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48. Abstract 3041: Blood-brain barrier penetrating ATM inhibitor (AZ32) radiosensitises intracranial gliomas in mice

Author

Durant, Steve T., primary, Karlin, Jeremy, additional, Pike, Kurt, additional, Colclough, Nicola, additional, Mukhopadhyay, N, additional, Ahmad, S F., additional, Bekta, J M., additional, Tokarz, M, additional, Bardelle, Catherine, additional, Hughes, Gareth, additional, Patel, Bhavika, additional, Thomason, Andrew, additional, Cadogan, Elaine, additional, Barrett, Ian, additional, Lau, Alan, additional, Pass, Martin, additional, and Valerie, Kristoffer, additional

Published
2016
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49. Expanding the Armory: Predicting and Tuning Covalent Warhead Reactivity

Author

Lonsdale, Richard, Burgess, Jonathan, Colclough, Nicola, Davies, Nichola L., Lenz, Eva M., Orton, Alexandra L., and Ward, Richard A.

Abstract

Targeted covalent inhibition is an established approach for increasing the potency and selectivity of potential drug candidates, as well as identifying potent and selective tool compounds for target validation studies. It is evident that identification of reversible recognition elements is essential for selective covalent inhibition, but this must also be achieved with the appropriate level of inherent reactivity of the reactive functionality (or “warhead”). Structural changes that increase or decrease warhead reactivity, guided by methods to predict the effect of those changes, have the potential to tune warhead reactivity and negate issues related to potency and/or toxicity. The half-life to adduct formation with glutathione (GSH t1/2) is a useful assay for measuring the reactivity of cysteine-targeting covalent warheads but is limited to synthesized molecules. In this manuscript we assess the ability of several experimental and computational approaches to predict GSH t1/2for a range of cysteine targeting warheads, including a novel method based on pKa. Furthermore, matched molecular pairs analysis has been performed against our internal compound collection, revealing structure–activity relationships between a selection of different covalent warheads. These observations and methods of prediction will be valuable in the design of new covalent inhibitors with desired levels of reactivity.

Published
2024
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50. Utilization of Structure-Based Design to Identify Novel, Irreversible Inhibitors of EGFR Harboring the T790M Mutation

Author

Hennessy, Edward J., primary, Chuaqui, Claudio, additional, Ashton, Susan, additional, Colclough, Nicola, additional, Cross, Darren A. E., additional, Debreczeni, Judit É., additional, Eberlein, Cath, additional, Gingipalli, Lakshmaiah, additional, Klinowska, Teresa C. M., additional, Orme, Jonathan P., additional, Sha, Li, additional, and Wu, Xiaoyun, additional

Published
2016
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