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Your search keyword '"Wythes, Martin"' showing total 29 results
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29 results on '"Wythes, Martin"'

1. Synthesis of macrocyclic, potential protease inhibitors using a generic scaffold

Author

Dumez, Estelle, Snaith, John S., Jackson, Richard F. W., McElroy, Andrew B., Overington, John, Wythes, Martin J., Withka, Jane M., and McLellan, Thomas J.

Subjects
Chemistry, Organic -- Research, Cyclic compounds -- Physiological aspects, Proteases -- Physiological aspects, Chemical inhibitors -- Physiological aspects, Enzymes -- Physiological aspects, Peptides -- Physiological aspects, Biological sciences, Chemistry
Abstract

Research has been conducted on the macrocyclic peptides, potential proteinase inhibitors. The study of the generic structure of these peptides has been carried out using the structures of the known enzyme-inhibitor complexes.

Published
2002

2. A new approach to the synthesis of beta-hydroxy-alpha-amino acids using (arylthio)nitrooxiranes

Author

Jackson, Richard F.W., Palmer, Nicholas J., Wythes, Martin J., Clegg, William, and Elsegood, Mark R.G.

Subjects
Amino acids -- Synthesis, Chemical reactions -- Observations, Biological sciences, Chemistry
Abstract

The stereospecific reactions between enantiomerically and diastereoisomerically pure 2-(arylthio)-2-nitrooxiranes and ammonia is a stereocontrolled pathway to beta-hydroxy-alpha-amino acids with configurational inversion. Nucleophilic epoxidation of 1-(arylthio)-1-nitroalkenes by anhydrous metal alkyl peroxides lead to 2-(arylthio) in tetrahydrofuran.

Published
1995

3. Preparation of enantiomerically pure protected 4-oxo-alpha-amino acids and 3-aryl-alpha-amino acids from serine

Author

Jackson, Richard F.W., Wishart, Neil, Wood, Anthony a, James, Keith, and Wythes, Martin J.

Subjects
Organic compounds -- Synthesis, Chemical tests and reagents -- Research, Anions -- Research, Serine -- Usage, Alanine -- Usage, Zinc compounds -- Usage, Amino acids -- Synthesis, Biological sciences, Chemistry
Abstract

An organozinc reagent obtained by ultrasonication of protected beta-iodo alanine serves as a practical alanine beta-anion. In the presence of bis(triphenylphosphine)palladium chloride, it can be acylated with acid chlorides to give protected 4-oxo-alpha amino acids in up to 90% yield. In the presence of bis(tri-o-tolylphosphine)palladium dichloride, it couples with aryl iodides to form protected 3-aryl-alpha-amino acids in up to 67% yield. Both oxo and aryl products are enantiomerically pure and may be deprotected with ease, either at the carboxyl or amino ends, to provide synthons for peptide synthesis.

Published
1992

4. Selective, Small-Molecule Co-Factor Binding Site Inhibition of a Su(var)3–9, Enhancer of Zeste, Trithorax Domain Containing Lysine Methyltransferase.

Author

Taylor, Alexandria P., Swewczyk, Magdalena, Kennedy, Steven, Trush, Viacheslav V., Wu, Hong, Zeng, Hong, Dong, Aiping, Ferreira de Freitas, Renato, Tatlock, John, Kumpf, Robert A., Wythes, Martin, Casimiro-Garcia, Agustin, Denny, Rajiah Aldrin, Parikh, Mihir D., Li, Fengling, Barsyte-Lovejoy, Dalia, Schapira, Matthieu, Vedadi, Masoud, Brown, Peter J., and Arrowsmith, Cheryl H.

Published
2019
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5. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two: National Harbor, MD, USA. 9-13 November 2016

Author

Ager, Casey, Reilley, Matthew, Nicholas, Courtney, Bartkowiak, Todd, Jaiswal, Ashvin, Curran, Michael, Albershardt, Tina C., Bajaj, Anshika, Archer, Jacob F., Reeves, Rebecca S., Ngo, Lisa Y., Berglund, Peter, ter Meulen, Jan, Denis, Caroline, Ghadially, Hormas, Arnoux, Thomas, Chanuc, Fabien, Fuseri, Nicolas, Wilkinson, Robert W., Wagtmann, Nicolai, Morel, Yannis, Andre, Pascale, Atkins, Michael B., Carlino, Matteo S., Ribas, Antoni, Thompson, John A., Choueiri, Toni K., Hodi, F. Stephen, Hwu, Wen-Jen, McDermott, David F., Atkinson, Victoria, Cebon, Jonathan S., Fitzharris, Bernie, Jameson, Michael B., McNeil, Catriona, Hill, Andrew G., Mangin, Eric, Ahamadi, Malidi, van Vugt, Marianne, van Zutphen, Mariëlle, Ibrahim, Nageatte, Long, Georgina V., Gartrell, Robyn, Blake, Zoe, Simoes, Ines, Fu, Yichun, Saito, Takuro, Qian, Yingzhi, Lu, Yan, Saenger, Yvonne M., Budhu, Sadna, De Henau, Olivier, Zappasodi, Roberta, Schlunegger, Kyle, Freimark, Bruce, Hutchins, Jeff, Barker, Christopher A., Wolchok, Jedd D., Merghoub, Taha, Burova, Elena, Allbritton, Omaira, Hong, Peter, Dai, Jie, Pei, Jerry, Liu, Matt, Kantrowitz, Joel, Lai, Venus, Poueymirou, William, MacDonald, Douglas, Ioffe, Ella, Mohrs, Markus, Olson, William, Thurston, Gavin, Capasso, Cristian, Frascaro, Federica, Carpi, Sara, Tähtinen, Siri, Feola, Sara, Fusciello, Manlio, Peltonen, Karita, Martins, Beatriz, Sjöberg, Madeleine, Pesonen, Sari, Ranki, Tuuli, Kyruk, Lukasz, Ylösmäki, Erkko, Cerullo, Vincenzo, Cerignoli, Fabio, Xi, Biao, Guenther, Garret, Yu, Naichen, Muir, Lincoln, Zhao, Leyna, Abassi, Yama, Cervera-Carrascón, Víctor, Siurala, Mikko, Santos, João, Havunen, Riikka, Parviainen, Suvi, Hemminki, Akseli, Dalgleish, Angus, Mudan, Satvinder, DeBenedette, Mark, Plachco, Ana, Gamble, Alicia, Grogan, Elizabeth W., Krisko, John, Tcherepanova, Irina, Nicolette, Charles, Dhupkar, Pooja, Yu, Ling, Kleinerman, Eugenie S., Gordon, Nancy, Grenga, Italia, Lepone, Lauren, Gameiro, Sofia, Knudson, Karin M., Fantini, Massimo, Tsang, Kwong, Hodge, James, Donahue, Renee, Schlom, Jeffrey, Evans, Elizabeth, Bussler, Holm, Mallow, Crystal, Reilly, Christine, Torno, Sebold, Scrivens, Maria, Foster, Cathie, Howell, Alan, Balch, Leslie, Knapp, Alyssa, Leonard, John E., Paris, Mark, Fisher, Terry, Hu-Lieskovan, Siwen, Smith, Ernest, Zauderer, Maurice, Fogler, William, Franklin, Marilyn, Thayer, Matt, Saims, Dan, Magnani, John L., Gong, Jian, Gray, Michael, Fromm, George, de Silva, Suresh, Giffin, Louise, Xu, Xin, Rose, Jason, Schreiber, Taylor H., Gameiro, Sofia R., Clavijo, Paul E., Allen, Clint T., Hodge, James W., Tsang, Kwong Y., Grogan, Jane, Manieri, Nicholas, Chiang, Eugene, Caplazi, Patrick, Yadav, Mahesh, Hagner, Patrick, Chiu, Hsiling, Waldman, Michelle, Klippel, Anke, Thakurta, Anjan, Pourdehnad, Michael, Gandhi, Anita, Henrich, Ian, Quick, Laura, Young, Rob, Chou, Margaret, Hotson, Andrew, Willingham, Stephen, Ho, Po, Choy, Carmen, Laport, Ginna, McCaffery, Ian, Miller, Richard, Tipton, Kimberly A., Wong, Kenneth R., Singson, Victoria, Wong, Chihunt, Chan, Chanty, Huang, Yuanhiu, Liu, Shouchun, Richardson, Jennifer H., Kavanaugh, W. Michael, West, James, Irving, Bryan A., Jaini, Ritika, Loya, Matthew, Eng, Charis, Johnson, Melissa L., Adjei, Alex A., Opyrchal, Mateusz, Ramalingam, Suresh, Janne, Pasi A., Dominguez, George, Gabrilovich, Dmitry, de Leon, Laura, Hasapidis, Jeannette, Diede, Scott J., Ordentlich, Peter, Cruickshank, Scott, Meyers, Michael L., Hellmann, Matthew D., Kalinski, Pawel, Zureikat, Amer, Edwards, Robert, Muthuswamy, Ravi, Obermajer, Nataša, Urban, Julie, Butterfield, Lisa H., Gooding, William, Zeh, Herbert, Bartlett, David, Zubkova, Olga, Agapova, Larissa, Kapralova, Marina, Krasovskaia, Liudmila, Ovsepyan, Armen, Lykov, Maxim, Eremeev, Artem, Bokovanov, Vladimir, Grigoryeva, Olga, Karpov, Andrey, Ruchko, Sergey, Shuster, Alexandr, Khalil, Danny N., Campesato, Luis Felipe, Li, Yanyun, Lazorchak, Adam S., Patterson, Troy D., Ding, Yueyun, Sasikumar, Pottayil, Sudarshan, Naremaddepalli, Gowda, Nagaraj, Ramachandra, Raghuveer, Samiulla, Dodheri, Giri, Sanjeev, Eswarappa, Rajesh, Ramachandra, Murali, Tuck, David, Wyant, Timothy, Leshem, Jasmin, Liu, Xiu-fen, Bera, Tapan, Terabe, Masaki, Bossenmaier, Birgit, Niederfellner, Gerhard, Reiter, Yoram, Pastan, Ira, Xia, Leiming, Xia, Yang, Hu, Yangyang, Wang, Yi, Bao, Yangyi, Dai, Fu, Huang, Shiang, Hurt, Elaine, Hollingsworth, Robert E., Lum, Lawrence G., Chang, Alfred E., Wicha, Max S., Li, Qiao, Mace, Thomas, Makhijani, Neil, Talbert, Erin, Young, Gregory, Guttridge, Denis, Conwell, Darwin, Lesinski, Gregory B., Gonzales, Rodney JM Macedo, Huffman, Austin P., Wang, Ximi K., Reshef, Ran, MacKinnon, Andy, Chen, Jason, Gross, Matt, Marguier, Gisele, Shwonek, Peter, Sotirovska, Natalija, Steggerda, Susanne, Parlati, Francesco, Makkouk, Amani, Bennett, Mark K., Emberley, Ethan, Huang, Tony, Li, Weiqun, Neou, Silinda, Pan, Alison, Zhang, Jing, Zhang, Winter, Marshall, Netonia, Marron, Thomas U., Agudo, Judith, Brown, Brian, Brody, Joshua, McQuinn, Christopher, Farren, Matthew, Komar, Hannah, Shakya, Reena, Ludwug, Thomas, Morillon, Y. Maurice, Hammond, Scott A., Greiner, John W., Nath, Pulak R., Schwartz, Anthony L., Maric, Dragan, Roberts, David D., Naing, Aung, Papadopoulos, Kyriakos P., Autio, Karen A., Wong, Deborah J., Patel, Manish, Falchook, Gerald, Pant, Shubham, Ott, Patrick A., Whiteside, Melinda, Patnaik, Amita, Mumm, John, Janku, Filip, Chan, Ivan, Bauer, Todd, Colen, Rivka, VanVlasselaer, Peter, Brown, Gail L., Tannir, Nizar M., Oft, Martin, Infante, Jeffrey, Lipson, Evan, Gopal, Ajay, Neelapu, Sattva S., Armand, Philippe, Spurgeon, Stephen, Leonard, John P., Sanborn, Rachel E., Melero, Ignacio, Gajewski, Thomas F., Maurer, Matthew, Perna, Serena, Gutierrez, Andres A., Clynes, Raphael, Mitra, Priyam, Suryawanshi, Satyendra, Gladstone, Douglas, Callahan, Margaret K., Crooks, James, Brown, Sheila, Gauthier, Audrey, de Boisferon, Marc Hillairet, MacDonald, Andrew, Brunet, Laura Rosa, Rothwell, William T., Bell, Peter, Wilson, James M., Sato-Kaneko, Fumi, Yao, Shiyin, Zhang, Shannon S., Carson, Dennis A., Guiducci, Cristina, Coffman, Robert L., Kitaura, Kazutaka, Matsutani, Takaji, Suzuki, Ryuji, Hayashi, Tomoko, Cohen, Ezra E. W., Schaer, David, Li, Yanxia, Dobkin, Julie, Amatulli, Michael, Hall, Gerald, Doman, Thompson, Manro, Jason, Dorsey, Frank Charles, Sams, Lillian, Holmgaard, Rikke, Persaud, Krishnadatt, Ludwig, Dale, Surguladze, David, Kauh, John S., Novosiadly, Ruslan, Kalos, Michael, Driscoll, Kyla, Pandha, Hardev, Ralph, Christy, Harrington, Kevin, Curti, Brendan, Akerley, Wallace, Gupta, Sumati, Melcher, Alan, Mansfield, David, Kaufman, David R., Schmidt, Emmett, Grose, Mark, Davies, Bronwyn, Karpathy, Roberta, Shafren, Darren, Shamalov, Katerina, Cohen, Cyrille, Sharma, Naveen, Allison, James, Shekarian, Tala, Valsesia-Wittmann, Sandrine, Caux, Christophe, Marabelle, Aurelien, Slomovitz, Brian M., Moore, Kathleen M., Youssoufian, Hagop, Posner, Marshall, Tewary, Poonam, Brooks, Alan D., Xu, Ya-Ming, Wijeratne, Kithsiri, Gunatilaka, Leslie A. A., Sayers, Thomas J., Vasilakos, John P., Alston, Tesha, Dovedi, Simon, Elvecrog, James, Grigsby, Iwen, Herbst, Ronald, Johnson, Karen, Moeckly, Craig, Mullins, Stefanie, Siebenaler, Kristen, SternJohn, Julius, Tilahun, Ashenafi, Tomai, Mark A., Vogel, Katharina, Vietsch, Eveline E., Wellstein, Anton, Wythes, Martin, Crosignani, Stefano, Tumang, Joseph, Alekar, Shilpa, Bingham, Patrick, Cauwenberghs, Sandra, Chaplin, Jenny, Dalvie, Deepak, Denies, Sofie, De Maeseneire, Coraline, Feng, JunLi, Frederix, Kim, Greasley, Samantha, Guo, Jie, Hardwick, James, Kaiser, Stephen, Jessen, Katti, Kindt, Erick, Letellier, Marie-Claire, Li, Wenlin, Maegley, Karen, Marillier, Reece, Miller, Nichol, Murray, Brion, Pirson, Romain, Preillon, Julie, Rabolli, Virginie, Ray, Chad, Ryan, Kevin, Scales, Stephanie, Srirangam, Jay, Solowiej, Jim, Stewart, Al, Streiner, Nicole, Torti, Vince, Tsaparikos, Konstantinos, Zheng, Xianxian, Driessens, Gregory, Gomes, Bruno, Kraus, Manfred, Xu, Chunxiao, Zhang, Yanping, Kradjian, Giorgio, Qin, Guozhong, Qi, Jin, Xu, Xiaomei, Marelli, Bo, Yu, Huakui, Guzman, Wilson, Tighe, Rober, Salazar, Rachel, Lo, Kin-Ming, English, Jessie, Radvanyi, Laszlo, Lan, Yan, Postow, Michael, Senbabaoglu, Yasin, Gasmi, Billel, Zhong, Hong, Liu, Cailian, Hirschhorhn-Cymerman, Daniel, Zha, Yuanyuan, Malnassy, Gregory, Fulton, Noreen, Park, Jae-Hyun, Stock, Wendy, Nakamura, Yusuke, Liu, Hongtao, Ju, Xiaoming, Kosoff, Rachelle, Ramos, Kimberly, Coder, Brandon, Petit, Robert, Princiotta, Michael, Perry, Kyle, Zou, Jun, Arina, Ainhoa, Fernandez, Christian, Zheng, Wenxin, Beckett, Michael A., Mauceri, Helena J., Fu, Yang-Xin, Weichselbaum, Ralph R., Lewis, Whitney, Han, Yanyan, Wu, Yeting, Yang, Chou, Huang, Jing, Wu, Dongyun, Li, Jin, Liang, Xiaoling, Zhou, Xiangjun, Hou, Jinlin, Hassan, Raffit, Jahan, Thierry, Antonia, Scott J., Kindler, Hedy L., Alley, Evan W., Honarmand, Somayeh, Liu, Weiqun, Leong, Meredith L., Whiting, Chan C., Nair, Nitya, Enstrom, Amanda, Lemmens, Edward E., Tsujikawa, Takahiro, Kumar, Sushil, Coussens, Lisa M., Murphy, Aimee L., Brockstedt, Dirk G., Koch, Sven D., Sebastian, Martin, Weiss, Christian, Früh, Martin, Pless, Miklos, Cathomas, Richard, Hilbe, Wolfgang, Pall, Georg, Wehler, Thomas, Alt, Jürgen, Bischoff, Helge, Geissler, Michael, Griesinger, Frank, Kollmeier, Jens, Papachristofilou, Alexandros, Doener, Fatma, Fotin-Mleczek, Mariola, Hipp, Madeleine, Hong, Henoch S., Kallen, Karl-Josef, Klinkhardt, Ute, Stosnach, Claudia, Scheel, Birgit, Schroeder, Andreas, Seibel, Tobias, Gnad-Vogt, Ulrike, Zippelius, Alfred, Park, Ha-Ram, Ahn, Yong-Oon, Kim, Tae Min, Kim, Soyeon, Kim, Seulki, Lee, Yu Soo, Keam, Bhumsuk, Kim, Dong-Wan, Heo, Dae Seog, Pilon-Thomas, Shari, Weber, Amy, Morse, Jennifer, Kodumudi, Krithika, Liu, Hao, Mullinax, John, Sarnaik, Amod A., Pike, Luke, Bang, Andrew, Balboni, Tracy, Taylor, Allison, Spektor, Alexander, Wilhite, Tyler, Krishnan, Monica, Cagney, Daniel, Alexander, Brian, Aizer, Ayal, Buchbinder, Elizabeth, Awad, Mark, Ghandi, Leena, Schoenfeld, Jonathan, Lessey-Morillon, Elizabeth, Ridnour, Lisa, Segal, Neil H., Sharma, Manish, Le, Dung T., Ferris, Robert L., Zelenetz, Andrew D., Levy, Ronald, Lossos, Izidore S., Jacobson, Caron, Ramchandren, Radhakrishnan, Godwin, John, Colevas, A. Dimitrios, Meier, Roland, Krishnan, Suba, Gu, Xuemin, Neely, Jaclyn, Timmerman, John, Vanpouille-Box, Claire I., Formenti, Silvia C., Demaria, Sandra, Wennerberg, Erik, Mediero, Aranzazu, Cronstein, Bruce N., Gustafson, Michael P., DiCostanzo, AriCeli, Wheatley, Courtney, Kim, Chul-Ho, Bornschlegl, Svetlana, Gastineau, Dennis A., Johnson, Bruce D., Dietz, Allan B., MacDonald, Cameron, Bucsek, Mark, Qiao, Guanxi, Hylander, Bonnie, Repasky, Elizabeth, Turbitt, William J., Xu, Yitong, Mastro, Andrea, Rogers, Connie J., Withers, Sita, Wang, Ziming, Khuat, Lam T., Dunai, Cordelia, Blazar, Bruce R., Longo, Dan, Rebhun, Robert, Grossenbacher, Steven K., Monjazeb, Arta, Murphy, William J., Rowlinson, Scott, Agnello, Giulia, Alters, Susan, Lowe, David, Scharping, Nicole, Menk, Ashley V., Whetstone, Ryan, Zeng, Xue, Delgoffe, Greg M., Santos, Patricia M., Shi, Jian, Delgoffe, Greg, Nagasaka, Misako, Sukari, Ammar, Byrne-Steele, Miranda, Pan, Wenjing, Hou, Xiaohong, Brown, Brittany, Eisenhower, Mary, Han, Jian, Collins, Natalie, Manguso, Robert, Pope, Hans, Shrestha, Yashaswi, Boehm, Jesse, Haining, W. Nicholas, Cron, Kyle R., Sivan, Ayelet, Aquino-Michaels, Keston, Orecchioni, Marco, Bedognetti, Davide, Hendrickx, Wouter, Fuoco, Claudia, Spada, Filomena, Sgarrella, Francesco, Cesareni, Gianni, Marincola, Francesco, Kostarelos, Kostas, Bianco, Alberto, Delogu, Lucia, Roelands, Jessica, Boughorbel, Sabri, Decock, Julie, Presnell, Scott, Wang, Ena, Marincola, Franco M., Kuppen, Peter, Ceccarelli, Michele, Rinchai, Darawan, Chaussabel, Damien, Miller, Lance, Nguyen, Andrew, Sanborn, J. Zachary, Vaske, Charles, Rabizadeh, Shahrooz, Niazi, Kayvan, Benz, Steven, Patel, Shashank, Restifo, Nicholas, White, James, Angiuoli, Sam, Sausen, Mark, Jones, Sian, Sevdali, Maria, Simmons, John, Velculescu, Victor, Diaz, Luis, Zhang, Theresa, Sims, Jennifer S., Barton, Sunjay M., Kadenhe-Chiweshe, Angela, Dela Cruz, Filemon, Turk, Andrew T., Mazzeo, Christopher F., Kung, Andrew L., Bruce, Jeffrey N., Yamashiro, Darrell J., Connolly, Eileen P., Baird, Jason, Crittenden, Marka, Friedman, David, Xiao, Hong, Leidner, Rom, Bell, Bryan, Young, Kristina, Gough, Michael, Bian, Zhen, Kidder, Koby, Liu, Yuan, Curran, Emily, Chen, Xiufen, Corrales, Leticia P., Kline, Justin, Aguilar, Ethan G., Guerriero, Jennifer, Sotayo, Alaba, Ponichtera, Holly, Pourzia, Alexandra, Schad, Sara, Carrasco, Ruben, Lazo, Suzan, Bronson, Roderick, Letai, Anthony, Kornbluth, Richard S., Gupta, Sachin, Termini, James, Guirado, Elizabeth, Stone, Geoffrey W., Meyer, Christina, Helming, Laura, Wilson, Nicholas, Hofmeister, Robert, Neubert, Natalie J., Tillé, Laure, Barras, David, Soneson, Charlotte, Baumgaertner, Petra, Rimoldi, Donata, Gfeller, David, Delorenzi, Mauro, Fuertes Marraco, Silvia A., Speiser, Daniel E., Abraham, Tara S., Xiang, Bo, Magee, Michael S., Waldman, Scott A., Snook, Adam E., Blogowski, Wojciech, Zuba-Surma, Ewa, Budkowska, Marta, Salata, Daria, Dolegowska, Barbara, Starzynska, Teresa, Chan, Leo, Somanchi, Srinivas, McCulley, Kelsey, Lee, Dean, Buettner, Nico, Shi, Feng, Myers, Paisley T., Curbishley, Stuart, Penny, Sarah A., Steadman, Lora, Millar, David, Speers, Ellen, Ruth, Nicola, Wong, Gabriel, Thimme, Robert, Adams, David, Cobbold, Mark, Thomas, Remy, Al-Muftah, Mariam, Wong, Michael KK, Morse, Michael, Clark, Joseph I., Kaufman, Howard L., Daniels, Gregory A., Hua, Hong, Rao, Tharak, Dutcher, Janice P., Kang, Kai, Saunthararajah, Yogen, Velcheti, Vamsidhar, Kumar, Vikas, Anwar, Firoz, Verma, Amita, Chheda, Zinal, Kohanbash, Gary, Sidney, John, Okada, Kaori, Shrivastav, Shruti, Carrera, Diego A., Liu, Shuming, Jahan, Naznin, Mueller, Sabine, Pollack, Ian F., Carcaboso, Angel M., Sette, Alessandro, Hou, Yafei, Okada, Hideho, Field, Jessica J., Zeng, Weiping, Shih, Vincent FS, Law, Che-Leung, Senter, Peter D., Gardai, Shyra J., Okeley, Nicole M., Abelin, Jennifer G., Saeed, Abu Z., Malaker, Stacy A., Shabanowitz, Jeffrey, Ward, Stephen T., Hunt, Donald F., Profusek, Pam, Wood, Laura, Shepard, Dale, Grivas, Petros, Kapp, Kerstin, Volz, Barbara, Oswald, Detlef, Wittig, Burghardt, Schmidt, Manuel, Sefrin, Julian P., Hillringhaus, Lars, Lifke, Valeria, Lifke, Alexander, Skaletskaya, Anna, Ponte, Jose, Chittenden, Thomas, Setiady, Yulius, Sivado, Eva, Thomas, Vincent, El Alaoui, Meddy, Papot, Sébastien, Dumontet, Charles, Dyson, Mike, McCafferty, John, El Alaoui, Said, Bommareddy, Praveen K., Zloza, Andrew, Kohlhapp, Frederick, Silk, Ann W., Jhawar, Sachin, Paneque, Tomas, Newman, Jenna, Beltran, Pedro, Cao, Felicia, Hong, Bang-Xing, Rodriguez-Cruz, Tania, Song, Xiao-Tong, Gottschalk, Stephen, Calderon, Hugo, Illingworth, Sam, Brown, Alice, Fisher, Kerry, Seymour, Len, Champion, Brian, Eriksson, Emma, Wenthe, Jessica, Hellström, Ann-Charlotte, Paul-Wetterberg, Gabriella, Loskog, Angelica, Milenova, Ioanna, Ståhle, Magnus, Jarblad-Leja, Justyna, Ullenhag, Gustav, Dimberg, Anna, Moreno, Rafael, Alemany, Ramon, Goyal, Sharad, Silk, Ann, Mehnert, Janice, Gabrail, Nashat, Bryan, Jennifer, Medina, Daniel, Mitchell, Leah, Yagiz, Kader, Lopez, Fernando, Mendoza, Daniel, Munday, Anthony, Gruber, Harry, Jolly, Douglas, Fuhrmann, Steven, Radoja, Sasa, Tan, Wei, Pourchet, Aldo, Frey, Alan, Mohr, Ian, Mulvey, Matthew, Andtbacka, Robert H. I., Ross, Merrick, Agarwala, Sanjiv, Grossmann, Kenneth, Taylor, Matthew, Vetto, John, Neves, Rogerio, Daud, Adil, Khong, Hung, Meek, Stephanie M., Ungerleider, Richard, Welden, Scott, Tanaka, Maki, Williams, Matthew, Hallmeyer, Sigrun, Fox, Bernard, Feng, Zipei, Paustian, Christopher, Bifulco, Carlo, Zafar, Sadia, Hemminki, Otto, Bramante, Simona, Vassilev, Lotta, Wang, Hongjie, Lieber, Andre, Hemmi, Silvio, de Gruijl, Tanja, Kanerva, Anna, Ansari, Tameem, Sundararaman, Srividya, Roen, Diana, Lehmann, Paul, Bloom, Anja C., Bender, Lewis H., Walters, Ian B., Berzofsky, Jay A., Chapelin, Fanny, Ahrens, Eric T., DeFalco, Jeff, Harbell, Michael, Manning-Bog, Amy, Scholz, Alexander, Zhang, Danhui, Baia, Gilson, Tan, Yann Chong, Sokolove, Jeremy, Kim, Dongkyoon, Williamson, Kevin, Chen, Xiaomu, Colrain, Jillian, Santo, Gregg Espiritu, Nguyen, Ngan, Volkmuth, Wayne, Greenberg, Norman, Robinson, William, Emerling, Daniel, Drake, Charles G., Petrylak, Daniel P., Antonarakis, Emmanuel S., Kibel, Adam S., Chang, Nancy N., Vu, Tuyen, Campogan, Dwayne, Haynes, Heather, Trager, James B., Sheikh, Nadeem A., Quinn, David I., Kirk, Peter, Addepalli, Murali, Chang, Thomas, Zhang, Ping, Konakova, Marina, Hagihara, Katsunobu, Pai, Steven, VanderVeen, Laurie, Obalapur, Palakshi, Kuo, Peiwen, Quach, Phi, Fong, Lawrence, Charych, Deborah H., Zalevsky, Jonathan, Langowski, John L., Kirksey, Yolanda, Nutakki, Ravi, Kolarkar, Shalini, Pena, Rhoneil, Hoch, Ute, Doberstein, Stephen K., Cha, John, Mallon, Zach, Perez, Myra, McDaniel, Amanda, Anand, Snjezana, Uecker, Darrin, Nuccitelli, Richard, Wieckowski, Eva, Muthuswamy, Ravikumar, Ravindranathan, Roshni, Renrick, Ariana N., Thounaojam, Menaka, Thomas, Portia, Pellom, Samuel, Shanker, Anil, Dudimah, Duafalia, Brooks, Alan, Su, Yu-Lin, Adamus, Tomasz, Zhang, Qifang, Nechaev, Sergey, Kortylewski, Marcin, Wei, Spencer, Anderson, Clark, Tang, Chad, Schoenhals, Jonathan, Tsouko, Efrosini, Heymach, John, de Groot, Patricia, Chang, Joe, Hess, Kenneth R., Diab, Adi, Sharma, Padmanee, Hong, David, Welsh, James, Parsons, Andrea J., Leleux, Jardin, Ascarateil, Stephane, Koziol, Marie Eve, Bai, Dina, Dai, Peihong, Wang, Weiyi, Yang, Ning, Shuman, Stewart, Deng, Liang, Dillon, Patrick, Petroni, Gina, Brenin, David, Bullock, Kim, Olson, Walter, Smolkin, Mark E., Smith, Kelly, Nail, Carmel, Slingluff, Craig L., Sharma, Meenu, Fa’ak, Faisal, Janssen, Louise, Khong, Hiep, Xiao, Zhilan, Hailemichael, Yared, Singh, Manisha, Vianden, Christina, Overwijk, Willem W., Facciabene, Andrea, Stefano, Pierini, Chongyung, Fang, Rafail, Stavros, Nielsen, Michael, Vanderslice, Peter, Woodside, Darren G., Market, Robert V., Biediger, Ronald J., Marathi, Upendra K., Hollevoet, Kevin, Geukens, Nick, Declerck, Paul, Joly, Nathalie, McIntosh, Laura, Paramithiotis, Eustache, Rizell, Magnus, Sternby, Malin, Andersson, Bengt, Karlsson-Parra, Alex, Kuai, Rui, Ochyl, Lukasz, Schwendeman, Anna, Moon, James, Deng, Weiwen, Hudson, Thomas E., Hanson, Bill, Rae, Chris S., Burrill, Joel, Skoble, Justin, Katibah, George, deVries, Michele, Lauer, Peter, Dubensky, Thomas W., Chen, Xin, Zhou, Li, Ren, Xiubao, Aggarwal, Charu, Mangrolia, Drishty, Cohen, Roger, Weinstein, Gregory, Morrow, Matthew, Bauml, Joshua, Kraynyak, Kim, Boyer, Jean, Yan, Jian, Lee, Jessica, Humeau, Laurent, Oyola, Sandra, Duff, Susan, Weiner, David, Yang, Zane, Bagarazzi, Mark, McNeel, Douglas G., Eickhoff, Jens, Jeraj, Robert, Staab, Mary Jane, Straus, Jane, Rekoske, Brian, Liu, Glenn, Melssen, Marit, Grosh, William, Varhegyi, Nikole, Galeassi, Nadejda, Deacon, Donna H., Gaughan, Elizabeth, Ghisoli, Maurizio, Barve, Minal, Mennel, Robert, Wallraven, Gladice, Manning, Luisa, Senzer, Neil, Nemunaitis, John, Ogasawara, Masahiro, Ota, Shuichi, Peace, Kaitlin M., Hale, Diane F., Vreeland, Timothy J., Jackson, Doreen O., Berry, John S., Trappey, Alfred F., Herbert, Garth S., Clifton, Guy T., Hardin, Mark O., Toms, Anne, Qiao, Na, Litton, Jennifer, Peoples, George E., Mittendorf, Elizabeth A., Ghamsari, Lila, Flano, Emilio, Jacques, Judy, Liu, Biao, Havel, Jonathan, Makarov, Vladimir, Chan, Timothy A., Flechtner, Jessica B., Facciponte, John, Ugel, Stefano, De Sanctis, Francesco, Coukos, George, Paris, Sébastien, Pottier, Agnes, Levy, Laurent, Lu, Bo, Cappuccini, Federica, Pollock, Emily, Bryant, Richard, Hamdy, Freddie, Hill, Adrian, Redchenko, Irina, Sultan, Hussein, Kumai, Takumi, Fesenkova, Valentyna, Celis, Esteban, Fernando, Ingrid, Palena, Claudia, David, Justin M., Gabitzsch, Elizabeth, Jones, Frank, Gulley, James L., Herranz, Mireia Uribe, Wada, Hiroshi, Shimizu, Atsushi, Osada, Toshihiro, Fukaya, Satoshi, Sasaki, Eiji, Abolhalaj, Milad, Askmyr, David, Lundberg, Kristina, Albrekt, Ann-Sofie, Greiff, Lennart, Lindstedt, Malin, Flies, Dallas B., Higuchi, Tomoe, Ornatowski, Wojciech, Harris, Jaryse, Adams, Sarah F., Aguilera, Todd, Rafat, Marjan, Castellini, Laura, Shehade, Hussein, Kariolis, Mihalis, Jang, Dadi, vonEbyen, Rie, Graves, Edward, Ellies, Lesley, Rankin, Erinn, Koong, Albert, Giaccia, Amato, Ajina, Reham, Wang, Shangzi, Smith, Jill, Pierobon, Mariaelena, Jablonski, Sandra, Petricoin, Emanuel, Weiner, Louis M., Sherry, Lorcan, Waller, John, Anderson, Mark, Bigley, Alison, Bernatchez, Chantale, Haymaker, Cara, Kluger, Harriet, Tetzlaff, Michael, Jackson, Natalie, Gergel, Ivan, Tagliaferri, Mary, Hwu, Patrick, Snzol, Mario, Hurwitz, Michael, Barberi, Theresa, Martin, Allison, Suresh, Rahul, Barakat, David, Harris-Bookman, Sarah, Drake, Charles, Friedman, Alan, Berkey, Sara, Downs-Canner, Stephanie, Edwards, Robert P., Curiel, Tyler, Odunsi, Kunle, Bruno, Tullia C., Moore, Brandon, Squalls, Olivia, Ebner, Peggy, Waugh, Katherine, Mitchell, John, Franklin, Wilbur, Merrick, Daniel, McCarter, Martin, Palmer, Brent, Kern, Jeffrey, Vignali, Dario, Slansky, Jill, Chan, Anissa S. H., Qiu, Xiaohong, Fraser, Kathryn, Jonas, Adria, Ottoson, Nadine, Gordon, Keith, Kangas, Takashi O., Leonardo, Steven, Ertelt, Kathleen, Walsh, Richard, Uhlik, Mark, Graff, Jeremy, Bose, Nandita, Gupta, Ravi, Mandloi, Nitin, Paul, Kiran, Patil, Ashwini, Sathian, Rekha, Mohan, Aparna, Manoharan, Malini, Chaudhuri, Amitabha, Chen, Yu, Lin, Jing, Ye, Yun-bin, Xu, Chun-wei, Chen, Gang, Guo, Zeng-qing, Komarov, Andrey, Chenchik, Alex, Makhanov, Michael, Frangou, Costa, Zheng, Yi, Coltharp, Carla, Unfricht, Darryn, Dilworth, Ryan, Fridman, Leticia, Liu, Linying, Rajopadhye, Milind, Miller, Peter, Concha-Benavente, Fernando, Bauman, Julie, Trivedi, Sumita, Srivastava, Raghvendra, Ohr, James, Heron, Dwight, Duvvuri, Uma, Kim, Seungwon, Torrey, Heather, Mera, Toshi, Okubo, Yoshiaki, Vanamee, Eva, Foster, Rosemary, Faustman, Denise, Stack, Edward, Izaki, Daisuke, Beck, Kristen, Jia, Dan Tong, Armenta, Paul, White-Stern, Ashley, Marks, Douglas, Taback, Bret, Horst, Basil, Glickman, Laura Hix, Kanne, David B., Gauthier, Kelsey S., Desbien, Anthony L., Francica, Brian, Leong, Justin L., Sung, Leonard, Metchette, Ken, Kasibhatla, Shailaja, Pferdekamper, Anne Marie, Zheng, Lianxing, Cho, Charles, Feng, Yan, McKenna, Jeffery M., Tallarico, John, Bender, Steven, Ndubaku, Chudi, McWhirter, Sarah M., Gugel, Elena Gonzalez, Bell, Charles J. M., Munk, Adiel, Muniz, Luciana, Bhardwaj, Nina, Zhao, Fei, Evans, Kathy, Xiao, Christine, Holtzhausen, Alisha, Hanks, Brent A., Scholler, Nathalie, Yin, Catherine, Van der Meijs, Pien, Prantner, Andrew M., Krejsa, Cecile M., Smith, Leia, Johnson, Brian, Branstetter, Daniel, Stein, Paul L., Jaen, Juan C., Tan, Joanne BL, Chen, Ada, Park, Timothy, Powers, Jay P., Sexton, Holly, Xu, Guifen, Young, Steve W., Schindler, Ulrike, Deng, Wentao, Klinke, David John, Komar, Hannah M., Serpa, Gregory, Elnaggar, Omar, Hart, Philip, Schmidt, Carl, Dillhoff, Mary, Jin, Ming, Ostrowski, Michael C., Koti, Madhuri, Au, Katrina, Peterson, Nichole, Truesdell, Peter, Reid-Schachter, Gillian, Graham, Charles, Craig, Andrew, Francis, Julie-Ann, Kotlan, Beatrix, Balatoni, Timea, Farkas, Emil, Toth, Laszlo, Ujhelyi, Mihaly, Savolt, Akos, Doleschall, Zoltan, Horvath, Szabolcs, Eles, Klara, Olasz, Judit, Csuka, Orsolya, Kasler, Miklos, Liszkay, Gabriella, Barnea, Eytan, Blakely, Collin, Flynn, Patrick, Goodman, Reid, Bueno, Raphael, Sugarbaker, David, Jablons, David, Broaddus, V. Courtney, West, Brian, Kunk, Paul R., Obeid, Joseph M., Winters, Kevin, Pramoonjago, Patcharin, Stelow, Edward B., Bauer, Todd W., Rahma, Osama E., Lamble, Adam, Kosaka, Yoko, Huang, Fei, Saser, Kate A., Adams, Homer, Tognon, Christina E., Laderas, Ted, McWeeney, Shannon, Loriaux, Marc, Tyner, Jeffery W., Druker, Brian J., Lind, Evan F., Liu, Zhuqing, Lu, Shanhong, Kane, Lawrence P., Shayan, Gulidanna, Femel, Julia, Lane, Ryan, Booth, Jamie, Lund, Amanda W., Rodriguez, Anthony, Engelhard, Victor H., Metelli, Alessandra, Wu, Bill X., Fugle, Caroline W., Saleh, Rachidi, Sun, Shaoli, Wu, Jennifer, Liu, Bei, Li, Zihai, Morris, Zachary S., Guy, Emily I., Heinze, Clinton, Kler, Jasdeep, Gressett, Monica M., Werner, Lauryn R., Gillies, Stephen D., Korman, Alan J., Loibner, Hans, Hank, Jacquelyn A., Rakhmilevich, Alexander L., Harari, Paul M., Sondel, Paul M., Huelsmann, Erica, Broucek, Joseph, Brech, Dorothee, Straub, Tobias, Irmler, Martin, Beckers, Johannes, Buettner, Florian, Schaeffeler, Elke, Schwab, Matthias, Noessner, Elfriede, Wolfreys, Alison, Da Costa, Andre, Silva, John, Crosby, Andrea, Staelens, Ludovicus, Craggs, Graham, Cauvin, Annick, Mason, Sean, Paterson, Alison M., Lake, Andrew C., Armet, Caroline M., O’Connor, Rachel W., Hill, Jonathan A., Normant, Emmanuel, Adam, Ammar, Biniszkiewicz, Detlev M., Chappel, Scott C., Palombella, Vito J., Holland, Pamela M., Becker, Annette, Leleti, Manmohan R., Newcomb, Eric, Tan, Joanne B. L., Rapisuwon, Suthee, Radfar, Arash, Gardner, Kellie, Gibney, Geoffrey, Atkins, Michael, Rennier, Keith R., Crowder, Robert, Wang, Ping, Pachynski, Russell K., Carrero, Rosa M. Santana, Rivas, Sarai, Beceren-Braun, Figen, Anthony, Scott, Schluns, Kimberly S., Sawant, Deepali, Chikina, Maria, Yano, Hiroshi, Workman, Creg, Salerno, Elise, Mauldin, Ileana, Deacon, Donna, Shea, Sofia, Pinczewski, Joel, Gajewski, Thomas, Spranger, Stefani, Horton, Brendan, Suzuki, Akiko, Leland, Pamela, Joshi, Bharat H., Puri, Raj K., Sweis, Randy F., Bao, Riyue, Luke, Jason, Theodoraki, Marie-Nicole, Mogundo, Frances-Mary, Won, Haejung, Moreira, Dayson, Gao, Chan, Zhao, Xingli, Duttagupta, Priyanka, Jones, Jeremy, D’Apuzzo, Massimo, and Pal, Sumanta

Published
2016
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20. Discovery of Highly Selective Inhibitors of Microtubule-Associated Serine/Threonine Kinase-like (MASTL).

Author

Gallego RA, Scales S, Toledo C, Auth M, Bernier L, Berry M, Brun S, Chung L, Davis C, Diehl W, Dress K, Eisele K, Elleraas J, Ewanicki J, Fobian Y, Greasley S, Greenwald EC, Johnson TW, Khamphavong P, Lafontaine J, Li J, Linton A, Maestre M, Miller N, Murtaza A, Patman RL, Quinlan CL, Ramms DJ, Richardson P, Sach N, Salomon-Ferrer R, Silva F, Timofeevski S, Tran P, Tran-Dubé M, Wang F, Wang W, Wythes M, Yang S, Zou A, VanArsdale T, and McAlpine I

Subjects
Humans, Structure-Activity Relationship, Cell Line, Tumor, Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Cell Proliferation drug effects, Models, Molecular, Drug Discovery, Mice, Drug Design, Microtubule-Associated Proteins metabolism, Microtubule-Associated Proteins antagonists & inhibitors, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases metabolism, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors chemical synthesis
Abstract

By virtue of its role in cellular proliferation, microtubule-associated serine/threonine kinase-like (MASTL) represents a novel target and a first-in-class (FIC) opportunity to provide a new impactful therapeutic agent to oncology patients. Herein, we describe a hit-to-lead optimization effort that resulted in the delivery of two highly selective MASTL inhibitors. Key strategies leveraged to enable this work included structure-based drug design (SBDD), analysis of lipophilic efficiency (LipE) and novel synthesis. The resulting advanced lead compounds enabled a tumor growth inhibition study which was pivotal in assessing the potential value of MASTL as an oncology therapeutic target.

Published
2024
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21. SAM-Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance.

Author

Jensen-Pergakes K, Tatlock J, Maegley KA, McAlpine IJ, McTigue M, Xie T, Dillon CP, Wang Y, Yamazaki S, Spiegel N, Shi M, Nemeth A, Miller N, Hendrickson E, Lam H, Sherrill J, Chung CY, McMillan EA, Bryant SK, Palde P, Braganza J, Brooun A, Deng YL, Goshtasbi V, Kephart SE, Kumpf RA, Liu W, Patman RL, Rui E, Scales S, Tran-Dube M, Wang F, Wythes M, and Paul TA

Subjects
Animals, Apoptosis, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Cell Proliferation, Drug Resistance, Female, Humans, Lung Neoplasms pathology, Mice, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Protein-Arginine N-Methyltransferases antagonists & inhibitors, S-Adenosylmethionine metabolism
Abstract

Protein arginine methyltransferase 5 (PRMT5) overexpression in hematologic and solid tumors methylates arginine residues on cellular proteins involved in important cancer functions including cell-cycle regulation, mRNA splicing, cell differentiation, cell signaling, and apoptosis. PRMT5 methyltransferase function has been linked with high rates of tumor cell proliferation and decreased overall survival, and PRMT5 inhibitors are currently being explored as an approach for targeting cancer-specific dependencies due to PRMT5 catalytic function. Here, we describe the discovery of potent and selective S-adenosylmethionine (SAM) competitive PRMT5 inhibitors, with in vitro and in vivo characterization of clinical candidate PF-06939999. Acquired resistance mechanisms were explored through the development of drug resistant cell lines. Our data highlight compound-specific resistance mutations in the PRMT5 enzyme that demonstrate structural constraints in the cofactor binding site that prevent emergence of complete resistance to SAM site inhibitors. PRMT5 inhibition by PF-06939999 treatment reduced proliferation of non-small cell lung cancer (NSCLC) cells, with dose-dependent decreases in symmetric dimethyl arginine (SDMA) levels and changes in alternative splicing of numerous pre-mRNAs. Drug sensitivity to PF-06939999 in NSCLC cells associates with cancer pathways including MYC, cell cycle and spliceosome, and with mutations in splicing factors such as RBM10. Translation of efficacy in mouse tumor xenograft models with splicing mutations provides rationale for therapeutic use of PF-06939999 in the treatment of splicing dysregulated NSCLC., (©2021 American Association for Cancer Research.)

Published
2022
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22. Characterization of the Selective Indoleamine 2,3-Dioxygenase-1 (IDO1) Catalytic Inhibitor EOS200271/PF-06840003 Supports IDO1 as a Critical Resistance Mechanism to PD-(L)1 Blockade Therapy.

Author

Gomes B, Driessens G, Bartlett D, Cai D, Cauwenberghs S, Crosignani S, Dalvie D, Denies S, Dillon CP, Fantin VR, Guo J, Letellier MC, Li W, Maegley K, Marillier R, Miller N, Pirson R, Rabolli V, Ray C, Streiner N, Torti VR, Tsaparikos K, Van den Eynde BJ, Wythes M, Yao LC, Zheng X, Tumang J, and Kraus M

Subjects
Animals, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal, Humanized, Antineoplastic Agents pharmacology, B7-H1 Antigen metabolism, CTLA-4 Antigen metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Female, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism, Interferon-gamma metabolism, Kynurenine blood, Lymphocytes, Tumor-Infiltrating drug effects, Mice, Inbred BALB C, Mice, Inbred C57BL, Stereoisomerism, Substrate Specificity drug effects, T-Lymphocytes cytology, T-Lymphocytes drug effects, B7-H1 Antigen antagonists & inhibitors, Biocatalysis, Enzyme Inhibitors pharmacology, Immunotherapy, Indoleamine-Pyrrole 2,3,-Dioxygenase antagonists & inhibitors, Indoles pharmacology, Succinimides pharmacology
Abstract

Tumors use indoleamine 2,3-dioxygenase-1 (IDO1) as a major mechanism to induce an immunosuppressive microenvironment. IDO1 expression is upregulated in many cancers and considered to be a resistance mechanism to immune checkpoint therapies. IDO1 is induced in response to inflammatory stimuli such as IFNγ and promotes immune tolerance by depleting tryptophan and producing tryptophan catabolites, including kynurenine, in the tumor microenvironment. This leads to effector T-cell anergy and enhanced T reg function through upregulation of FoxP3. As a nexus for the induction of key immunosuppressive mechanisms, IDO1 represents an important immunotherapeutic target in oncology. Here, we report the identification and characterization of the novel selective, orally bioavailable IDO1 inhibitor EOS200271/PF-06840003. It reversed IDO1-induced T-cell anergy in vitro In mice carrying syngeneic tumor grafts, PF-06840003 reduced intratumoral kynurenine levels by over 80% and inhibited tumor growth both in monotherapy and, with an increased efficacy, in combination with antibodies blocking the immune checkpoint ligand PD-L1. We demonstrate that anti-PD-L1 therapy results in increased IDO1 metabolic activity thereby providing additional mechanistic rationale for combining PD-(L)1 blockade with IDO1 inhibition in cancer immunotherapies. Supported by these preclinical data and favorable predicted human pharmacokinetic properties of PF-06840003, a phase I open-label, multicenter clinical study (NCT02764151) has been initiated., (©2018 American Association for Cancer Research.)

Published
2018
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23. Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497).

Author

Kung PP, Bingham P, Brooun A, Collins M, Deng YL, Dinh D, Fan C, Gajiwala KS, Grantner R, Gukasyan HJ, Hu W, Huang B, Kania R, Kephart SE, Krivacic C, Kumpf RA, Khamphavong P, Kraus M, Liu W, Maegley KA, Nguyen L, Ren S, Richter D, Rollins RA, Sach N, Sharma S, Sherrill J, Spangler J, Stewart AE, Sutton S, Uryu S, Verhelle D, Wang H, Wang S, Wythes M, Xin S, Yamazaki S, Zhu H, Zhu J, Zehnder L, and Edwards M

Subjects
Administration, Oral, Biological Availability, Cell Line, Tumor, Humans, Isoquinolines administration & dosage, Isoquinolines chemistry, Models, Molecular, Molecular Conformation, Drug Design, Enhancer of Zeste Homolog 2 Protein antagonists & inhibitors, Isoquinolines pharmacokinetics, Isoquinolines pharmacology
Abstract

A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp 3 hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated log D (clogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23a exhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23a in complex with the three-protein PRC2 complex enabled understanding of the key structural features required for optimal binding.

Published
2018
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24. Discovery of a Novel and Selective Indoleamine 2,3-Dioxygenase (IDO-1) Inhibitor 3-(5-Fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (EOS200271/PF-06840003) and Its Characterization as a Potential Clinical Candidate.

Author

Crosignani S, Bingham P, Bottemanne P, Cannelle H, Cauwenberghs S, Cordonnier M, Dalvie D, Deroose F, Feng JL, Gomes B, Greasley S, Kaiser SE, Kraus M, Négrerie M, Maegley K, Miller N, Murray BW, Schneider M, Soloweij J, Stewart AE, Tumang J, Torti VR, Van Den Eynde B, and Wythes M

Subjects
Animals, Cell Line, Crystallography, X-Ray, Dogs, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacokinetics, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase chemistry, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism, Indoles chemistry, Indoles pharmacokinetics, Macaca fascicularis, Male, Mice, Molecular Docking Simulation, Rats, Structure-Activity Relationship, Succinimides chemistry, Succinimides pharmacokinetics, Enzyme Inhibitors pharmacology, Indoleamine-Pyrrole 2,3,-Dioxygenase antagonists & inhibitors, Indoles pharmacology, Succinimides pharmacology
Abstract

Tumors use tryptophan-catabolizing enzymes such as indoleamine 2,3-dioxygenase (IDO-1) to induce an immunosuppressive environment. IDO-1 is induced in response to inflammatory stimuli and promotes immune tolerance through effector T-cell anergy and enhanced Treg function. As such, IDO-1 is a nexus for the induction of a key immunosuppressive mechanism and represents an important immunotherapeutic target in oncology. Starting from HTS hit 5, IDO-1 inhibitor 6 (EOS200271/PF-06840003) has been developed. The structure-activity relationship around 6 is described and rationalized using the X-ray crystal structure of 6 bound to human IDO-1, which shows that 6, differently from most of the IDO-1 inhibitors described so far, does not bind to the heme iron atom and has a novel binding mode. Clinical candidate 6 shows good potency in an IDO-1 human whole blood assay and also shows a very favorable ADME profile leading to favorable predicted human pharmacokinetic properties, including a predicted half-life of 16-19 h.

Published
2017
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25. Correction to Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2H)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors.

Author

Kung PP, Rui E, Bergqvist S, Bingham P, Braganza J, Collins M, Cui M, Diehl W, Dinh D, Fan C, Fantin VR, Gukasyan HJ, Hu W, Huang B, Kephart S, Krivacic C, Kumpf RA, Li G, Maegley KA, McAlpine I, Nguyen L, Ninkovic S, Ornelas M, Ryskin M, Scales S, Sutton S, Tatlock J, Verhelle D, Wang F, Wells P, Wythes M, Yamazaki S, Yip B, Yu X, Zehnder L, Zhang WG, Rollins RA, and Edwards M

Published
2016
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26. Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2H)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors.

Author

Kung PP, Rui E, Bergqvist S, Bingham P, Braganza J, Collins M, Cui M, Diehl W, Dinh D, Fan C, Fantin VR, Gukasyan HJ, Hu W, Huang B, Kephart S, Krivacic C, Kumpf RA, Li G, Maegley KA, McAlpine I, Nguyen L, Ninkovic S, Ornelas M, Ryskin M, Scales S, Sutton S, Tatlock J, Verhelle D, Wang F, Wells P, Wythes M, Yamazaki S, Yip B, Yu X, Zehnder L, Zhang WG, Rollins RA, and Edwards M

Subjects
Animals, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Cyclization, Enhancer of Zeste Homolog 2 Protein metabolism, Female, Humans, Isoquinolines chemistry, Isoquinolines pharmacology, Isoquinolines therapeutic use, Lactams chemistry, Lactams pharmacology, Mice, Mice, SCID, Models, Molecular, Neoplasms drug therapy, Neoplasms metabolism, Pyridones therapeutic use, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Drug Design, Enhancer of Zeste Homolog 2 Protein antagonists & inhibitors, Pyridones chemistry, Pyridones pharmacology
Abstract

A new enhancer of zeste homolog 2 (EZH2) inhibitor series comprising a substituted phenyl ring joined to a dimethylpyridone moiety via an amide linkage has been designed. A preferential amide torsion that improved the binding properties of the compounds was identified for this series via computational analysis. Cyclization of the amide linker resulted in a six-membered lactam analogue, compound 18. This transformation significantly improved the ligand efficiency/potency of the cyclized compound relative to its acyclic analogue. Additional optimization of the lactam-containing EZH2 inhibitors focused on lipophilic efficiency (LipE) improvement, which provided compound 31. Compound 31 displayed improved LipE and on-target potency in both biochemical and cellular readouts relative to compound 18. Inhibitor 31 also displayed robust in vivo antitumor growth activity and dose-dependent de-repression of EZH2 target genes.

Published
2016
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27. Optimization of potent, selective, and orally bioavailable pyrrolodinopyrimidine-containing inhibitors of heat shock protein 90. Identification of development candidate 2-amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide.

Author

Zehnder L, Bennett M, Meng J, Huang B, Ninkovic S, Wang F, Braganza J, Tatlock J, Jewell T, Zhou JZ, Burke B, Wang J, Maegley K, Mehta PP, Yin MJ, Gajiwala KS, Hickey MJ, Yamazaki S, Smith E, Kang P, Sistla A, Dovalsantos E, Gehring MR, Kania R, Wythes M, and Kung PP

Subjects
Administration, Oral, Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Binding, Competitive, Biological Availability, Blood Proteins metabolism, Cell Line, Tumor, Cell Membrane Permeability, Drug Screening Assays, Antitumor, Drug Stability, Female, Humans, Hydrophobic and Hydrophilic Interactions, In Vitro Techniques, Male, Melanoma drug therapy, Melanoma pathology, Mice, Mice, Nude, Microsomes, Liver metabolism, Models, Molecular, Neoplasm Transplantation, Protein Binding, Pyrazoles pharmacokinetics, Pyrazoles pharmacology, Pyrimidines pharmacokinetics, Pyrimidines pharmacology, Rats, Structure-Activity Relationship, Transplantation, Heterologous, Antineoplastic Agents chemical synthesis, HSP90 Heat-Shock Proteins antagonists & inhibitors, Pyrazoles chemical synthesis, Pyrimidines chemical synthesis
Abstract

A novel class of heat shock protein 90 (Hsp90) inhibitors was discovered by high-throughput screening and was subsequently optimized using a combination of structure-based design, parallel synthesis, and the application of medicinal chemistry principles. Through this process, the biochemical and cell-based potency of the original HTS lead were substantially improved along with the corresponding metabolic stability properties. These efforts culminated with the identification of a development candidate (compound 42) which displayed desired PK/PD relationships, significant efficacy in a melanoma A2058 xenograft tumor model, and attractive DMPK profiles.

Published
2011
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28. Design of selective, ATP-competitive inhibitors of Akt.

Author

Freeman-Cook KD, Autry C, Borzillo G, Gordon D, Barbacci-Tobin E, Bernardo V, Briere D, Clark T, Corbett M, Jakubczak J, Kakar S, Knauth E, Lippa B, Luzzio MJ, Mansour M, Martinelli G, Marx M, Nelson K, Pandit J, Rajamohan F, Robinson S, Subramanyam C, Wei L, Wythes M, and Morris J

Subjects
Amides pharmacokinetics, Amides pharmacology, Aminoquinolines pharmacokinetics, Aminoquinolines pharmacology, Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Cell Line, Tumor, Crystallography, X-Ray, Dogs, Mice, Models, Molecular, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors pharmacology, Rats, Stereoisomerism, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Adenosine Triphosphate physiology, Amides chemical synthesis, Aminoquinolines chemical synthesis, Antineoplastic Agents chemical synthesis, Protein Kinase Inhibitors chemical synthesis, Proto-Oncogene Proteins c-akt antagonists & inhibitors
Abstract

This paper describes the design and synthesis of novel, ATP-competitive Akt inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include the discovery of an initial lead that was modestly selective and medicinal chemistry optimization of that lead to provide more selective analogues. Analysis of the data suggested that highly lipophilic analogues would likely suffer from poor overall properties. Central to the discussion is the concept of optimization of lipophilic efficiency and the ability to balance overall druglike propeties with the careful control of lipophilicity in the lead series. Discovery of the nonracemic amide series and subsequent modification produced an advanced analogue that performed well in advanced preclinical assays, including xenograft tumor growth inhibition studies, and this analogue was nominated for clinical development.

Published
2010
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29. 2-(6-Bromo-3-pyrid-yl)-8-methyl-imidazo[1,2-a]pyrazine.

Author

Huang B, Rui E, Wythes M, Kung PP, Moore C, Rheingold AL, and Yanovsky A

Abstract

The structure of the title compound, C(12)H(9)BrN(4), prepared by the reaction of 2-bromo-1-(6-bromo-3-pyrid-yl)ethanone with 2-amino-3-methyl-pyrazine indicates that the compound with the bromo-pyridyl substituent at position 2 of the imidazopyrazine fused-ring system represents the major product of this reaction. The plane of the pyridine ring forms a dihedral angle of 16.2 (2)° with the essentially planar (r.m.s. deviation = 0.006 Å) imidazopyrazine system. In the crystal, mol-ecules are linked by weak C-H⋯N inter-actions.

Published
2010
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