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355 results on '"Bountra, Chas"'

3. Clinical utility of a serum biomarker panel in distinguishing prostate cancer from benign prostate hyperplasia

Author

Kiebish, Michael A., Tekumalla, Poornima, Ravipaty, Shobha, Dobi, Albert, Srivastava, Shiv, Wu, Wenfang, Patil, Saurabh, Friss, Tracey, Klotz, Allison, Srinivasan, Alagarsamy, Cullen, Jennifer, Rosner, Inger L., Ali, Amina, Laszlo, Sandra, Petrovic, Michele, Fleshner, Neil, Garren, Jeonifer, Miller, Greg, Mahaveer Chand, Nischal, Rodrigues, Leonardo O., Granger, Elder, Kellogg, Mark D., Luan, Shen, Diamandis, Eleftherios, Akmaev, Viatcheslav R., Sarangarajan, Rangaprasad, Bountra, Chas, Freedland, Stephen J., McLeod, David G., and Narain, Niven R.

Published
2021
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4. The promise and peril of chemical probes

Author

Arrowsmith, Cheryl H, Audia, James E, Austin, Christopher, Baell, Jonathan, Bennett, Jonathan, Blagg, Julian, Bountra, Chas, Brennan, Paul E, Brown, Peter J, Bunnage, Mark E, Buser-Doepner, Carolyn, Campbell, Robert M, Carter, Adrian J, Cohen, Philip, Copeland, Robert A, Cravatt, Ben, Dahlin, Jayme L, Dhanak, Dashyant, Edwards, Aled M, Frederiksen, Mathias, Frye, Stephen V, Gray, Nathanael, Grimshaw, Charles E, Hepworth, David, Howe, Trevor, Huber, Kilian VM, Jin, Jian, Knapp, Stefan, Kotz, Joanne D, Kruger, Ryan G, Lowe, Derek, Mader, Mary M, Marsden, Brian, Mueller-Fahrnow, Anke, Müller, Susanne, O'Hagan, Ronan C, Overington, John P, Owen, Dafydd R, Rosenberg, Saul H, Ross, Ruth, Roth, Bryan, Schapira, Matthieu, Schreiber, Stuart L, Shoichet, Brian, Sundström, Michael, Superti-Furga, Giulio, Taunton, Jack, Toledo-Sherman, Leticia, Walpole, Chris, Walters, Michael A, Willson, Timothy M, Workman, Paul, Young, Robert N, and Zuercher, William J

Subjects
Generic health relevance, Biomedical Research, Humans, Information Dissemination, Intellectual Property, Internet, Molecular Probes, Molecular Weight, Sensitivity and Specificity, Small Molecule Libraries, Medicinal and Biomolecular Chemistry, Biochemistry and Cell Biology, Biochemistry & Molecular Biology
Abstract

Chemical probes are powerful reagents with increasing impacts on biomedical research. However, probes of poor quality or that are used incorrectly generate misleading results. To help address these shortcomings, we will create a community-driven wiki resource to improve quality and convey current best practice.

Published
2015

5. Building a roadmap for developing combination therapies for Alzheimers disease.

Author

Perry, Daniel, Sperling, Reisa, Katz, Russell, Berry, Donald, Dilts, David, Hanna, Debra, Salloway, Stephen, Trojanowski, John, Bountra, Chas, Krams, Michael, Luthman, Johan, Potkin, Steven, Gribkoff, Val, Temple, Robert, Wang, Yaning, Carrillo, Maria, Stephenson, Diane, Snyder, Heather, Liu, Enchi, Ware, Tony, McKew, John, Fields, F, Bain, Lisa, and Bens, Cynthia

Subjects
Alzheimer’ disease, co-development, collaboration, combination therapy, novel therapy, Alzheimer Disease, Animals, Clinical Trials as Topic, Disease Models, Animal, Drug Therapy, Combination, Humans, Information Dissemination, Models, Theoretical
Abstract

Combination therapy has proven to be an effective strategy for treating many of the worlds most intractable diseases. A growing number of investigators in academia, industry, regulatory agencies, foundations and advocacy organizations are interested in pursuing a combination approach to treating Alzheimers disease. A meeting co-hosted by the Accelerate Cure/Treatments for Alzheimers Disease Coalition, the Critical Path Institute and the Alzheimers Association addressed challenges in designing clinical trials to test multiple treatments in combination and outlined a roadmap for making such trials a reality.

Published
2015

6. A genetics-led approach defines the drug target landscape of 30 immune-related traits

Author

Fang, Hai, The ULTRA-DD Consortium, De Wolf, Hans, Knezevic, Bogdan, Burnham, Katie L., Osgood, Julie, Sanniti, Anna, Lledó Lara, Alicia, Kasela, Silva, De Cesco, Stephane, Wegner, Jörg K., Handunnetthi, Lahiru, McCann, Fiona E., Chen, Liye, Sekine, Takuya, Brennan, Paul E., Marsden, Brian D., Damerell, David, O’Callaghan, Chris A., Bountra, Chas, Bowness, Paul, Sundström, Yvonne, Milani, Lili, Berg, Louise, Göhlmann, Hinrich W., Peeters, Pieter J., Fairfax, Benjamin P., Sundström, Michael, and Knight, Julian C.

Published
2019
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7. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response

Author

Kruidenier, Laurens, Chung, Chun-wa, Cheng, Zhongjun, Liddle, John, Che, KaHing, Joberty, Gerard, Bantscheff, Marcus, Bountra, Chas, Bridges, Angela, Diallo, Hawa, Eberhard, Dirk, Hutchinson, Sue, Jones, Emma, Katso, Roy, Leveridge, Melanie, Mander, Palwinder K, Mosley, Julie, Ramirez-Molina, Cesar, Rowland, Paul, Schofield, Christopher J, Sheppard, Robert J, Smith, Julia E, Swales, Catherine, Tanner, Robert, Thomas, Pamela, Tumber, Anthony, Drewes, Gerard, Oppermann, Udo, Patel, Dinshaw J, Lee, Kevin, and Wilson, David M

Subjects
Clinical Research, Underpinning research, 1.1 Normal biological development and functioning, Amino Acid Sequence, Animals, Biocatalysis, Catalytic Domain, Cells, Cultured, Enzyme Inhibitors, Evolution, Molecular, Histones, Humans, Inhibitory Concentration 50, Jumonji Domain-Containing Histone Demethylases, Lysine, Macrophages, Methylation, Mice, Models, Molecular, Substrate Specificity, Tumor Necrosis Factor-alpha, General Science & Technology
Abstract

The jumonji (JMJ) family of histone demethylases are Fe2+- and α-ketoglutarate-dependent oxygenases that are essential components of regulatory transcriptional chromatin complexes. These enzymes demethylate lysine residues in histones in a methylation-state and sequence-specific context. Considerable effort has been devoted to gaining a mechanistic understanding of the roles of histone lysine demethylases in eukaryotic transcription, genome integrity and epigenetic inheritance, as well as in development, physiology and disease. However, because of the absence of any selective inhibitors, the relevance of the demethylase activity of JMJ enzymes in regulating cellular responses remains poorly understood. Here we present a structure-guided small-molecule and chemoproteomics approach to elucidating the functional role of the H3K27me3-specific demethylase subfamily (KDM6 subfamily members JMJD3 and UTX). The liganded structures of human and mouse JMJD3 provide novel insight into the specificity determinants for cofactor, substrate and inhibitor recognition by the KDM6 subfamily of demethylases. We exploited these structural features to generate the first small-molecule catalytic site inhibitor that is selective for the H3K27me3-specific JMJ subfamily. We demonstrate that this inhibitor binds in a novel manner and reduces lipopolysaccharide-induced proinflammatory cytokine production by human primary macrophages, a process that depends on both JMJD3 and UTX. Our results resolve the ambiguity associated with the catalytic function of H3K27-specific JMJs in regulating disease-relevant inflammatory responses and provide encouragement for designing small-molecule inhibitors to allow selective pharmacological intervention across the JMJ family.

Published
2012

8. Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells

Author

Tumber, Anthony, Nuzzi, Andrea, Hookway, Edward S., Hatch, Stephanie B., Velupillai, Srikannathasan, Johansson, Catrine, Kawamura, Akane, Savitsky, Pavel, Yapp, Clarence, Szykowska, Aleksandra, Wu, Na, Bountra, Chas, Strain-Damerell, Claire, Burgess-Brown, Nicola A., Ruda, Gian Filippo, Fedorov, Oleg, Munro, Shonagh, England, Katherine S., Nowak, Radoslaw P., Schofield, Christopher J., La Thangue, Nicholas B., Pawlyn, Charlotte, Davies, Faith, Morgan, Gareth, Athanasou, Nick, Müller, Susanne, Oppermann, Udo, and Brennan, Paul E.

Published
2017
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9. Supplemental Methods and References from Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy

Author

Picaud, Sarah, primary, Fedorov, Oleg, primary, Thanasopoulou, Angeliki, primary, Leonards, Katharina, primary, Jones, Katherine, primary, Meier, Julia, primary, Olzscha, Heidi, primary, Monteiro, Octovia, primary, Martin, Sarah, primary, Philpott, Martin, primary, Tumber, Anthony, primary, Filippakopoulos, Panagis, primary, Yapp, Clarence, primary, Wells, Christopher, primary, Che, Ka Hing, primary, Bannister, Andrew, primary, Robson, Samuel, primary, Kumar, Umesh, primary, Parr, Nigel, primary, Lee, Kevin, primary, Lugo, Dave, primary, Jeffrey, Philip, primary, Taylor, Simon, primary, Vecellio, Matteo L., primary, Bountra, Chas, primary, Brennan, Paul E., primary, O'Mahony, Alison, primary, Velichko, Sharlene, primary, Müller, Susanne, primary, Hay, Duncan, primary, Daniels, Danette L., primary, Urh, Marjeta, primary, La Thangue, Nicholas B., primary, Kouzarides, Tony, primary, Prinjha, Rab, primary, Schwaller, Jürg, primary, and Knapp, Stefan, primary

Published
2023
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10. Supplementary Tables S1-S8 from Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy

Author

Picaud, Sarah, primary, Fedorov, Oleg, primary, Thanasopoulou, Angeliki, primary, Leonards, Katharina, primary, Jones, Katherine, primary, Meier, Julia, primary, Olzscha, Heidi, primary, Monteiro, Octovia, primary, Martin, Sarah, primary, Philpott, Martin, primary, Tumber, Anthony, primary, Filippakopoulos, Panagis, primary, Yapp, Clarence, primary, Wells, Christopher, primary, Che, Ka Hing, primary, Bannister, Andrew, primary, Robson, Samuel, primary, Kumar, Umesh, primary, Parr, Nigel, primary, Lee, Kevin, primary, Lugo, Dave, primary, Jeffrey, Philip, primary, Taylor, Simon, primary, Vecellio, Matteo L., primary, Bountra, Chas, primary, Brennan, Paul E., primary, O'Mahony, Alison, primary, Velichko, Sharlene, primary, Müller, Susanne, primary, Hay, Duncan, primary, Daniels, Danette L., primary, Urh, Marjeta, primary, La Thangue, Nicholas B., primary, Kouzarides, Tony, primary, Prinjha, Rab, primary, Schwaller, Jürg, primary, and Knapp, Stefan, primary

Published
2023
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11. Data from Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy

Author

Picaud, Sarah, primary, Fedorov, Oleg, primary, Thanasopoulou, Angeliki, primary, Leonards, Katharina, primary, Jones, Katherine, primary, Meier, Julia, primary, Olzscha, Heidi, primary, Monteiro, Octovia, primary, Martin, Sarah, primary, Philpott, Martin, primary, Tumber, Anthony, primary, Filippakopoulos, Panagis, primary, Yapp, Clarence, primary, Wells, Christopher, primary, Che, Ka Hing, primary, Bannister, Andrew, primary, Robson, Samuel, primary, Kumar, Umesh, primary, Parr, Nigel, primary, Lee, Kevin, primary, Lugo, Dave, primary, Jeffrey, Philip, primary, Taylor, Simon, primary, Vecellio, Matteo L., primary, Bountra, Chas, primary, Brennan, Paul E., primary, O'Mahony, Alison, primary, Velichko, Sharlene, primary, Müller, Susanne, primary, Hay, Duncan, primary, Daniels, Danette L., primary, Urh, Marjeta, primary, La Thangue, Nicholas B., primary, Kouzarides, Tony, primary, Prinjha, Rab, primary, Schwaller, Jürg, primary, and Knapp, Stefan, primary

Published
2023
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12. Supplemental Figures S1-S6 from Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy

Author

Picaud, Sarah, primary, Fedorov, Oleg, primary, Thanasopoulou, Angeliki, primary, Leonards, Katharina, primary, Jones, Katherine, primary, Meier, Julia, primary, Olzscha, Heidi, primary, Monteiro, Octovia, primary, Martin, Sarah, primary, Philpott, Martin, primary, Tumber, Anthony, primary, Filippakopoulos, Panagis, primary, Yapp, Clarence, primary, Wells, Christopher, primary, Che, Ka Hing, primary, Bannister, Andrew, primary, Robson, Samuel, primary, Kumar, Umesh, primary, Parr, Nigel, primary, Lee, Kevin, primary, Lugo, Dave, primary, Jeffrey, Philip, primary, Taylor, Simon, primary, Vecellio, Matteo L., primary, Bountra, Chas, primary, Brennan, Paul E., primary, O'Mahony, Alison, primary, Velichko, Sharlene, primary, Müller, Susanne, primary, Hay, Duncan, primary, Daniels, Danette L., primary, Urh, Marjeta, primary, La Thangue, Nicholas B., primary, Kouzarides, Tony, primary, Prinjha, Rab, primary, Schwaller, Jürg, primary, and Knapp, Stefan, primary

Published
2023
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15. Integrative analysis of GWAS and co-localisation data suggests novel genes associated with age-related multimorbidity

Author

West, Clare E., primary, Karim, Mohd, additional, Falaguera, Maria J., additional, Speidel, Leo, additional, Green, Charlotte J., additional, Logie, Lisa, additional, Schwartzentruber, Jeremy, additional, Ochoa, David, additional, Lord, Janet M., additional, Ferguson, Michael A. J., additional, Bountra, Chas, additional, Wilkinson, Graeme F., additional, Vaughan, Beverley, additional, Leach, Andrew R., additional, Dunham, Ian, additional, and Marsden, Brian D., additional

Published
2022
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18. Structures of ABCB10, a human ATP-binding cassette transporter in apo- and nucleotide-bound states

Author

Shintre, Chitra A., Pike, Ashley C. W., Li, Qiuhong, Kim, Jung-In, Barr, Alastair J., Goubin, Solenne, Shrestha, Leela, Yang, Jing, Berridge, Georgina, Ross, Jonathan, Stansfeld, Phillip J., Sansom, Mark S. P., Edwards, Aled M., Bountra, Chas, Marsden, Brian D., von Delft, Frank, Bullock, Alex N., Gileadi, Opher, Burgess-Brown, Nicola A., and Carpenter, Elisabeth P.

Published
2013

19. The Structural Basis of ZMPSTE24-Dependent Laminopathies

Author

Quigley, Andrew, Dong, Yin Yao, Pike, Ashley C. W., Dong, Liang, Shrestha, Leela, Berridge, Georgina, Stansfeld, Phillip J., Sansom, Mark S. P., Edwards, Aled M., Bountra, Chas, von Delft, Frank, Bullock, Alex N., Burgess-Brown, Nicola A., and Carpenter, Elisabeth P.

Published
2013
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20. Proteogenomic Metabolism Dependent Signature Identifies Worse Outcome in Breast And Other Cancers

Author

Wang, Guisong, primary, Shah, Punit, additional, Searfoss, Richard, additional, Liu, Jianfang, additional, Campbell, Jamie Leigh, additional, Deyarmin, Brenda, additional, Zingmark, Rebecca, additional, Mostoller, Bradley, additional, Kvecher, Leonid, additional, Somiari, Stella, additional, Raj-Kumar, Praveen-Kumar, additional, Sturtz, Lori, additional, Granger, Elder, additional, Vahdat, Linda, additional, Bountra, Chas, additional, Sarangarajan, Rangaprasad, additional, Cutler, Mary, additional, Narain, Niven, additional, Hooke, Jeffrey, additional, Shriver, Craig, additional, Hu, Hai, additional, Kiebish, Michael, additional, and Kovatich, Albert, additional

Published
2022
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22. Abstract 1188: Reclassification of ER+ (luminal A/luminal B1 minus ER low)-like and ER- like breast tumors based on proteomic/gene and clinical outcome signatures

Author

Wang, Guisong, primary, Shah, Punit, additional, Searfoss, Rick, additional, Fantacone-Campbell, Leigh, additional, Hooke, Jeffrey A., additional, Deyarmin, Brenda, additional, Zingmark, Rebecca N., additional, Somiari, Stella, additional, Liu, Jianfang, additional, Kvecher, Leonid, additional, Mostoller, Bradley, additional, Sturtz, Lori A., additional, Raj-Kumar, Praven-Kumar, additional, Granger, Elder, additional, Vahdat, Linda, additional, Cutler, Mary L., additional, Bountra, Chas, additional, Sarangarajan, Rangaprasad, additional, Hu, Hai, additional, Kiebish, Michael A., additional, Kovatich, Albert J., additional, Narain, Niven R., additional, and Shriver, Craig D., additional

Published
2021
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23. Abstract 2342: Multidimensional metabolomic stratification of ER+/HER2- compared to ER-/HER2- breast tumors

Author

Bussberg, Valerie, primary, Tolstikov, Vladimir, additional, Wang, Guisong, additional, Shah, Punit, additional, Searfoss, Rick, additional, Fantacone-Campbell, Leigh, additional, Hooke, Jeffrey A., additional, Deyarmin, Brenda, additional, Zingmark, Rebecca N., additional, Somiari, Stella, additional, Liu, Jianfang, additional, Kvecher, Leonid, additional, Mostoller, Bradley, additional, Sturtz, Lori, additional, Raj-Kumar, Praveen-Kumar, additional, Granger, Elder, additional, Vahdat, Linda, additional, Cutler, Mary L., additional, Bountra, Chas, additional, Sarangarajan, Rangaprasad, additional, Hu, Hai, additional, Kovatich, Albert J., additional, Kiebish, Michael A., additional, Narain, Niven R., additional, and Shriver, Craig D., additional

Published
2021
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26. Kruidenier et al. reply

Author

Kruidenier, Laurens, Chung, Chun-wa, Cheng, Zhongjun, Liddle, John, Che, KaHing, Joberty, Gerard, Bantscheff, Marcus, Bountra, Chas, Bridges, Angela, Diallo, Hawa, Eberhard, Dirk, Hutchinson, Sue, Jones, Emma, Katso, Roy, Leveridge, Melanie, Mander, Palwinder K., Mosley, Julie, Ramirez-Molina, Cesar, Rowland, Paul, Schofield, Christopher J., Sheppard, Robert J., Smith, Julia E., Swales, Catherine, Tanner, Robert, Thomas, Pamela, Tumber, Anthony, Drewes, Gerard, Oppermann, Udo, Patel, Dinshaw J., Lee, Kevin, and Wilson, David M.

Published
2014
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28. Bayesian Model Infers Drug Repurposing Candidates for Treatment of COVID-19

Author

Kiebish, Michael A., primary, Shah, Punit, additional, Sarangarajan, Rangaprasad, additional, Vishnudas, Vivek K., additional, Gesta, Stephane, additional, Tekumalla, Poornima K., additional, Bountra, Chas, additional, Granger, Elder, additional, Schadt, Eric, additional, Rodrigues, Leonardo O., additional, and Narain, Niven R., additional

Published
2021
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34. Bayesian model infers drug repurposing candidates for treatment of COVID-19

Author

Kiebish, Michael A., primary, Shah, Punit, additional, Sarangarajan, Rangaprasad, additional, Vishnudas, Vivek K., additional, Gesta, Stephane, additional, Tekumalla, Poornima K., additional, Bountra, Chas, additional, Granger, Elder, additional, Schadt, Eric, additional, Rodrigues, Leonardo O., additional, and Narain, Niven R., additional

Published
2020
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37. Abstract 2860: Impact of hemolysis on multi-omic pancreatic cancer biomarker discovery: De-risking precision medicine biomarker development

Author

Kiebish, Michael A., primary, Shah, Punit, additional, Bussberg, Valerie, additional, Tolstikov, Vladimir, additional, Searfoss, Rick, additional, Ofori-Mensa, Kennedy, additional, Grund, Eric M., additional, Darkwah, Abena, additional, Chen, Emily Y., additional, Greenwood, Bennett, additional, Ntoso, Ellaine Adu, additional, Rodrigues, Leonardo, additional, Liu, Mia, additional, Granger, Elder, additional, Bountra, Chas, additional, Sarangarajan, Rangaprasad, additional, Moser, A J., additional, and Narain, Niven R., additional

Published
2020
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43. A Chemical Probe for Tudor Domain Protein Spindlin1 to Investigate Chromatin Function.

Author

Fagan, Vincent, Johansson, Catrine, Gileadi, Carina, Monteiro, Octovia, Dunford, James Edward, Nibhani, Reshma, Philpott, Martin, Malzahn, Jessica, Wells, Graham, Farham, Ruth, Cribbs, Adam, Halidi, Nadia, Li, Fengling, Chau, Irene, Greschik, Holger, Velupillai, Srikannathasan, Allali-Hassani, Abdellah, Bennett, James M, Christott, Thomas, Giroud, Charline, Lewis, Andrew M, Huber, Kilian VM, Athanasou, Nick, Bountra, Chas, Jung, Manfred, Schüle, Roland, Vedadi, Masoud, Arrowsmith, Cheryl H, Xiong, Yan, Jin, Jian, Fedorov, Oleg, Farnie, Gillian, Brennan, Paul E, Oppermann, Udo CT, Fagan, Vincent, Johansson, Catrine, Gileadi, Carina, Monteiro, Octovia, Dunford, James Edward, Nibhani, Reshma, Philpott, Martin, Malzahn, Jessica, Wells, Graham, Farham, Ruth, Cribbs, Adam, Halidi, Nadia, Li, Fengling, Chau, Irene, Greschik, Holger, Velupillai, Srikannathasan, Allali-Hassani, Abdellah, Bennett, James M, Christott, Thomas, Giroud, Charline, Lewis, Andrew M, Huber, Kilian VM, Athanasou, Nick, Bountra, Chas, Jung, Manfred, Schüle, Roland, Vedadi, Masoud, Arrowsmith, Cheryl H, Xiong, Yan, Jin, Jian, Fedorov, Oleg, Farnie, Gillian, Brennan, Paul E, and Oppermann, Udo CT

Abstract

Modifications of histone tails, including lysine/arginine methylation, provide the basis of a 'chromatin or histone code'. Proteins that con-tain 'reader' domains can bind to these modifications and form specific effector complexes, which ultimately mediate chromatin function. The spindlin1 (SPIN1) protein contains three Tudor methyl-lysine/arginine reader domains and was identified as a putative onco-gene and transcriptional co-activator. Here we report a SPIN1 chemi-cal probe inhibitor with low nanomolar in vitro activity, exquisite selectivity on a panel of methyl reader and writer proteins, and with submicromolar cellular activity. X-ray crystallography showed that this Tudor domain chemical probe simultaneously engages Tudor domains 1 and 2 via a bidentate binding mode. Small molecule inhibition and siRNA knockdown of SPIN1, as well as chemoproteomic studies, iden-tified genes which are transcriptionally regulated by SPIN1 in squa-mous cell carcinoma and suggest that SPIN1 may have a roll in cancer related inflammation and/or cancer metastasis.

Published
2019

45. 8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine demethylase inhibitors

Author

Bavetsias, Vassilios, Lanigan, Rachel M., Ruda, Gian Filippo, Atrash, Butrus, McLaughlin, Mark G., Tumber, Anthony, Mok, N. Yi, Le Bihan, Yann-Vaï, Dempster, Sally, Boxall, Katherine J., Jeganathan, Fiona, Hatch, Stephanie B., Savitsky, Pavel, Velupillai, Srikannathasan, Krojer, Tobias, England, Katherine S., Sejberg, Jimmy, Thai, Ching, Donovan, Adam, Pal, Akos, Scozzafava, Giuseppe, Bennett, James M., Kawamura, Akane, Johansson, Catrine, Szykowska, Aleksandra, Gileadi, Carina, Burgess-Brown, Nicola A., von Delft, Frank, Oppermann, Udo, Walters, Zoe, Shipley, Janet, Raynaud, Florence I., Westaway, Susan M., Prinjha, Rab K., Fedorov, Oleg, Burke, Rosemary, Schofield, Christopher J., Westwood, Isaac M., Bountra, Chas, Müller, Susanne, van Montfort, Rob L. M., Brennan, Paul E., and Blagg, Julian

Subjects
Repressor Proteins, Jumonji Domain-Containing Histone Demethylases, Cell Membrane Permeability, Drug Discovery, Humans, Nuclear Proteins, Molecular Medicine, Pyrimidinones, Caco-2 Cells, Enzyme Inhibitors, Article
Abstract

We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.

Published
2016

47. A Chemical Probe for Tudor Domain Protein Spindlin1 to Investigate Chromatin Function

Author

Fagan, Vincent, primary, Johansson, Catrine, additional, Gileadi, Carina, additional, Monteiro, Octovia, additional, Dunford, James E., additional, Nibhani, Reshma, additional, Philpott, Martin, additional, Malzahn, Jessica, additional, Wells, Graham, additional, Faram, Ruth, additional, Cribbs, Adam P., additional, Halidi, Nadia, additional, Li, Fengling, additional, Chau, Irene, additional, Greschik, Holger, additional, Velupillai, Srikannathasan, additional, Allali-Hassani, Abdellah, additional, Bennett, James, additional, Christott, Thomas, additional, Giroud, Charline, additional, Lewis, Andrew M., additional, Huber, Kilian V. M., additional, Athanasou, Nick, additional, Bountra, Chas, additional, Jung, Manfred, additional, Schüle, Roland, additional, Vedadi, Masoud, additional, Arrowsmith, Cheryl, additional, Xiong, Yan, additional, Jin, Jian, additional, Fedorov, Oleg, additional, Farnie, Gillian, additional, Brennan, Paul E., additional, and Oppermann, Udo, additional

Published
2019
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48. Increased EZH2 expression in prostate cancer is associated with metastatic recurrence following external beam radiotherapy

Author

Wu, Xiaoning, primary, Scott, Helen, additional, Carlsson, Sigrid V., additional, Sjoberg, Daniel D., additional, Cerundolo, Lucia, additional, Lilja, Hans, additional, Prevo, Remko, additional, Rieunier, Guillaume, additional, Macaulay, Valentine, additional, Higgins, Geoffrey S., additional, Verrill, Clare L., additional, Lamb, Alastair D., additional, Cunliffe, Vincent T., additional, Bountra, Chas, additional, Hamdy, Freddie C., additional, and Bryant, Richard J., additional

Published
2019
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