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1. Phase I/II trial of RVU120, a CDK8/CDK19 inhibitor in patients with relapsed/refractory metastatic or advanced solid tumors

Author

Dziadziuszko, R., primary, Garralda Cabanas, E., additional, Rojas, K., additional, Chelstowska, M., additional, Blaszkowska, M., additional, Dudziak, R., additional, Rzymski, T., additional, Angelosanto, N., additional, Littlewood, P., additional, Nogai, H., additional, Boni, V., additional, and Lugowska, I., additional

Published
2022
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4. P501: CLI120-001 PHASE1B DOSE ESCALATION STUDY OF RVU120 IN PATIENTS WITH AML OR HIGH RISK MDS SAFETY AND EFFICACY DATA UPDATE

Author

Abboud, C., primary, Jan Maciej, Z., additional, Borthakur, G., additional, Solomon, S., additional, Howard, B., additional, Bradley, T., additional, Mouhayar, E., additional, Angelosanto, N., additional, Nogai, H., additional, Glasmacher, A., additional, Dudziak, R., additional, Brzozka, K., additional, Rzymski, T., additional, Littlewood, P., additional, and Maranda, E.-L., additional

Published
2022
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14. PF524 EVALUATION OF SERINE BIOSYNTHESIS PATHWAY AS A POTENTIAL THERAPEUTIC TARGET IN BURKITT LYMPHOMA

Author

Noyszewska-Kania, M., primary, Bialopiotrowicz, E., additional, Cybulska, M., additional, Grochowska, A., additional, Kopczynski, M., additional, Mikula, M., additional, Kachamakova-Trojanowska, N., additional, Loboda, A., additional, Prochorec-Sobieszek, M., additional, Szumera-Ciećkiewicz, A., additional, Firczuk, M., additional, Graczyk-Jarzynka, A., additional, Zagozdzon, R., additional, Zabek, A., additional, Mlynarz, P., additional, Gorniak, P., additional, Szydlowski, M., additional, Jablonska, E., additional, Polak, A., additional, Kowalczyk, P., additional, Piechna, K., additional, Rzymski, T., additional, Brzozka, K., additional, and Juszczynski, P., additional

Published
2019
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15. EVALUATION OF SERINE BIOSYNTHESIS PATHWAY AS A POTENTIAL THERAPEUTIC TARGET IN BURKITT LYMPHOMA

Author

Noyszewska-Kania, M., primary, Bialopiotrowicz, E., additional, Cybulska, M., additional, Grochowska, A., additional, Kopczynski, M., additional, Mikula, M., additional, Kachamakova-Trojanowska, N., additional, Loboda, A., additional, Prochorec-Sobieszek, M., additional, Szumera-Ciećkiewicz, A., additional, Firczuk, M., additional, Graczyk-Jarzynka, A., additional, Zagozdzon, R., additional, Zabek, A., additional, Mlynarz, P., additional, Gorniak, P., additional, Szydlowski, M., additional, Jablonska, E., additional, Polak, A., additional, Kowalczyk, P., additional, Piechna, K., additional, Rzymski, T., additional, Brzozka, K., additional, and Juszczynski, P., additional

Published
2019
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17. SEL120–34A, a specific, potent and orally bioavailable inhibitor of CDK8, targets STAT-dependent gene transcription in leukemia and lymphoma models

Author

Zylkiewicz, E., primary, Rzymski, T., additional, Mikula, M., additional, Dreas, A., additional, Wiklik, K., additional, Wrobel, A., additional, Golas, A., additional, Dolata, I., additional, Wojcik, K., additional, Masiejczyk, M., additional, Statkiewicz, M., additional, Kuklinska, U., additional, Goryca, K., additional, Grochowsk, A., additional, Cabaj, A., additional, Bialas, A., additional, Mikulski, M., additional, Windak, R., additional, Ostrowski, J., additional, and Brzozka, K., additional

Published
2016
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20. Poster session 3

Author

Nanka, O., primary, Krejci, E., additional, Pesevski, Z., additional, Sedmera, D., additional, Smart, N., additional, Rossdeutsch, A., additional, Dube, K. N., additional, Riegler, J., additional, Price, A. N., additional, Taylor, A., additional, Muthurangu, V., additional, Turner, M., additional, Lythgoe, M. F., additional, Riley, P. R., additional, Kryvorot, S., additional, Vladimirskaya, T., additional, Shved, I., additional, Schwarzl, M., additional, Seiler, S., additional, Huber, S., additional, Steendijk, P., additional, Maechler, H., additional, Truschnig-Wilders, M., additional, Pieske, B., additional, Post, H., additional, Caprio, C., additional, Baldini, A., additional, Chiavacci, E., additional, Dolfi, L., additional, Verduci, L., additional, Meghini, F., additional, Cremisi, F., additional, Pitto, L., additional, Kuan, T.-C., additional, Chen, M.-C., additional, Yang, T.-H., additional, Wu, W.-T., additional, Lin, C. S., additional, Rai, H., additional, Kumar, S., additional, Sharma, A. K., additional, Mastana, S., additional, Kapoor, A., additional, Pandey, C. M., additional, Agrawal, S., additional, Sinha, N., additional, Orlowska-Baranowska, E. H., additional, Placha, G., additional, Gora, J., additional, Baranowski, R., additional, Abramczuk, E., additional, Hryniewiecki, T., additional, Gaciong, Z., additional, Verschuren, J. J. W., additional, Wessels, J. A. M., additional, Trompet, S., additional, Stott, D. J., additional, Sattar, N., additional, Buckley, B., additional, Guchelaar, H. J., additional, Jukema, J. W., additional, Gharanei, M., additional, Hussain, A., additional, Mee, C. J., additional, Maddock, H. L., additional, Wijnen, W. J., additional, Van Den Oever, S., additional, Van Der Made, I., additional, Hiller, M., additional, Tijsen, A. J., additional, Pinto, Y. M., additional, Creemers, E. E., additional, Nikulina, S. U. Y., additional, Chernova, A., additional, Petry, A., additional, Rzymski, T., additional, Kracun, D., additional, Riess, F., additional, Pike, L., additional, Harris, A. L., additional, Gorlach, A., additional, Katare, R., additional, Oikawa, A., additional, Riu, F., additional, Beltrami, A. P., additional, Cesseli, D., additional, Emanueli, C., additional, Madeddu, P., additional, Zaglia, T., additional, Milan, G., additional, Franzoso, M., additional, Pesce, P., additional, Sarais, C., additional, Sandri, M., additional, Mongillo, M., additional, Butler, T. J., additional, Seymour, A.-M. L., additional, Ashford, D., additional, Jaffre, F., additional, Bussen, M., additional, Flohrschutz, I., additional, Martin, G. R., additional, Engelhardt, S., additional, Kararigas, G., additional, Nguyen, B. T., additional, Jarry, H., additional, Regitz-Zagrosek, V., additional, Van Bilsen, M., additional, Daniels, A., additional, Munts, C., additional, Janssen, B. J. A., additional, Van Der Vusse, G. J., additional, Van Nieuwenhoven, F. A., additional, Montalvo, C., additional, Villar, A. V., additional, Merino, D., additional, Garcia, R., additional, Llano, M., additional, Ares, M., additional, Hurle, M. A., additional, Nistal, J. F., additional, Dembinska-Kiec, A., additional, Beata Kiec-Wilk, B. K. W., additional, Anna Polus, A. P., additional, Urszula Czech, U. C., additional, Tatiana Konovaleva, T. K., additional, Gerd Schmitz, G. S., additional, Bertrand, L., additional, Balteau, M., additional, Timmermans, A., additional, Viollet, B., additional, Sakamoto, K., additional, Feron, O., additional, Horman, S., additional, Vanoverschelde, J. L., additional, Beauloye, C., additional, De Meester, C., additional, Martinez, E., additional, Martin, R., additional, Miana, M., additional, Jurado, R., additional, Gomez-Hurtado, N., additional, Bartolome, M. V., additional, San Roman, J. A., additional, Lahera, V., additional, Nieto, M. L., additional, Cachofeiro, V., additional, Rochais, F., additional, Sturny, R., additional, Mesbah, K., additional, Miquerol, L., additional, Kelly, R. G., additional, Messaoudi, S., additional, Gravez, B., additional, Tarjus, A., additional, Pelloux, V., additional, Samuel, J. L., additional, Delcayre, C., additional, Launay, J. M., additional, Clement, K., additional, Farman, N., additional, Jaisser, F., additional, Hadyanto, L., additional, Castellani, C., additional, Vescovo, G., additional, Ravara, B., additional, Tavano, R., additional, Pozzobon, M., additional, De Coppi, P., additional, Papini, E., additional, Vettor, R., additional, Thiene, G., additional, Angelini, A., additional, Meloni, M., additional, Caporali, A., additional, Cesselli, D., additional, Fortunato, O., additional, Avolio, E., additional, Schindler, R., additional, Simrick, S., additional, Brand, T., additional, Smart, N. S., additional, Herman, A., additional, Roura Ferrer, S., additional, Rodriguez Bago, J., additional, Soler-Botija, C., additional, Pujal, J. M., additional, Galvez-Monton, C., additional, Prat-Vidal, C., additional, Llucia-Valldeperas, A., additional, Blanco, J., additional, Bayes-Genis, A., additional, Foldes, G., additional, Maxime, M., additional, Ali, N. N., additional, Schneider, M. D., additional, Harding, S. E., additional, Reni, C., additional, Mangialardi, G., additional, De Pauw, A., additional, Sekkali, B., additional, Friart, A., additional, Ding, H., additional, Graffeuil, A., additional, Catalucci, D., additional, Balligand, J. L., additional, Azibani, F., additional, Tournoux, F., additional, Schlossarek, S., additional, Polidano, E., additional, Fazal, L., additional, Merval, R., additional, Carrier, L., additional, Chatziantoniou, C., additional, Buyandelger, B., additional, Linke, W., additional, Zou, P., additional, Kostin, S., additional, Ku, C., additional, Felkin, L., additional, Birks, E., additional, Barton, P., additional, Sattler, M., additional, Knoell, R., additional, Schroder, K., additional, Benkhoff, S., additional, Shimokawa, H., additional, Grisk, O., additional, Brandes, R. P., additional, Parepa, I. R., additional, Mazilu, L., additional, Suceveanu, A. I., additional, Suceveanu, A., additional, Rusali, L., additional, Cojocaru, L., additional, Matei, L., additional, Toringhibel, M., additional, Craiu, E., additional, Pires, A. L., additional, Pinho, M., additional, Pinho, S., additional, Sena, C., additional, Seica, R., additional, Leite-Moreira, A., additional, Dabroi, F., additional, Schiaffino, S., additional, Kiseleva, E., additional, Krukov, N., additional, Nikitin, O., additional, Ardatova, L., additional, Mourouzis, I., additional, Pantos, C., additional, Kokkinos, A. D., additional, Cokkinos, D. V., additional, Scoditti, E., additional, Massaro, M., additional, Carluccio, M. A., additional, Pellegrino, M., additional, Calabriso, N., additional, Gastaldelli, A., additional, Storelli, C., additional, De Caterina, R., additional, Lindner, D., additional, Zietsch, C., additional, Schultheiss, H.-P., additional, Tschope, C., additional, Westermann, D., additional, Everaert, B. R., additional, Nijenhuis, V. J., additional, Reith, F. C. M., additional, Hoymans, V. Y., additional, Timmermans, J. P., additional, Vrints, C. J., additional, Simova, I., additional, Mateev, H., additional, Katova, T., additional, Haralanov, L., additional, Dimitrov, N., additional, Mironov, N., additional, Golitsyn, S. P., additional, Sokolov, S. F., additional, Yuricheva, Y. U. A., additional, Maikov, E. B., additional, Shlevkov, N. B., additional, Rosenstraukh, L. V., additional, Chazov, E. I., additional, Radosinska, J., additional, Knezl, V., additional, Benova, T., additional, Slezak, J., additional, Urban, L., additional, Tribulova, N., additional, Virag, L., additional, Kristof, A., additional, Kohajda, Z. S., additional, Szel, T., additional, Husti, Z., additional, Baczko, I., additional, Jost, N., additional, Varro, A., additional, Sarusi, A., additional, Farkas, A. S., additional, Orosz, S. Z., additional, Forster, T., additional, Farkas, A., additional, Zakhrabova-Zwiauer, O. M., additional, Hardziyenka, M., additional, Nieuwland, R., additional, Tan, H. L., additional, Raaijmakers, A. J. A., additional, Bourgonje, V. J. A., additional, Kok, G. J. M., additional, Van Veen, A. A. B., additional, Anderson, M. E., additional, Vos, M. A., additional, Bierhuizen, M. F. A., additional, Benes, J., additional, Sebestova, B., additional, Ghouri, I. A., additional, Kemi, O. J., additional, Kelly, A., additional, Burton, F. L., additional, Smith, G. L., additional, Ozdemir, S., additional, Acsai, K., additional, Doisne, N., additional, Van Der Nagel, R., additional, Beekman, H. D. M., additional, Van Veen, T. A. B., additional, Sipido, K. R., additional, Antoons, G., additional, Harmer, S. C., additional, Mohal, J. S., additional, Kemp, D., additional, Tinker, A., additional, Beech, D., additional, Burley, D. S., additional, Cox, C. D., additional, Wann, K. T., additional, Baxter, G. F., additional, Wilders, R., additional, Verkerk, A., additional, Fragkiadaki, P., additional, Germanakis, G., additional, Tsarouchas, K., additional, Tsitsimpikou, C., additional, Tsardi, M., additional, George, D., additional, Tsatsakis, A., additional, Rodrigues, P., additional, Barros, C., additional, Najmi, A. K., additional, Khan, V., additional, Akhtar, M., additional, Pillai, K. K., additional, Mujeeb, M., additional, Aqil, M., additional, Bayliss, C. R., additional, Messer, A. E., additional, Leung, M.-C., additional, Ward, D., additional, Van Der Velden, J., additional, Poggesi, C., additional, Redwood, C. S., additional, Marston, S., additional, Vite, A., additional, Gandjbakhch, E., additional, Gary, F., additional, Fressart, V., additional, Leprince, P., additional, Fontaine, G., additional, Komajda, M., additional, Charron, P., additional, Villard, E., additional, Falcao-Pires, I., additional, Gavina, C., additional, Hamdani, N., additional, Stienen, G. J. M., additional, Niessens, H. W. M., additional, Leite-Moreira, A. F., additional, Paulus, W. J., additional, Memo, M., additional, Marston, S. B., additional, Vafiadaki, E., additional, Qian, J., additional, Arvanitis, D. A., additional, Sanoudou, D., additional, Kranias, E. G., additional, Elmstedt, N., additional, Lind, B., additional, Ferm-Widlund, K., additional, Westgren, M., additional, Brodin, L.-A., additional, Mansfield, C., additional, West, T., additional, Ferenczi, M., additional, Wijnker, P. J. M., additional, Foster, D. B., additional, Coulter, A., additional, Frazier, A., additional, Murphy, A. M., additional, Shah, M., additional, Sikkel, M. B., additional, Desplantez, T., additional, Collins, T. P., additional, O' Gara, P., additional, Lyon, A. R., additional, Macleod, K. T., additional, Ottesen, A. H., additional, Louch, W. E., additional, Carlson, C., additional, Landsverk, O. J. B., additional, Stridsberg, M., additional, Sjaastad, I., additional, Oie, E., additional, Omland, T., additional, Christensen, G., additional, Rosjo, H., additional, Cartledge, J., additional, Clark, L. A., additional, Ibrahim, M., additional, Siedlecka, U., additional, Navaratnarajah, M., additional, Yacoub, M. H., additional, Camelliti, P., additional, Terracciano, C. M., additional, Chester, A., additional, Gonzalez-Tendero, A., additional, Torre, I., additional, Garcia-Garcia, F., additional, Dopazo, J., additional, Gratacos, E., additional, Taylor, D., additional, Bhandari, S., additional, Seymour, A.-M., additional, Fliegner, D., additional, Jost, J., additional, Bugger, H., additional, Ventura-Clapier, R., additional, Carpi, A., additional, Campesan, M., additional, Canton, M., additional, Menabo, R., additional, Pelicci, P. G., additional, Giorgio, M., additional, Di Lisa, F., additional, Hancock, M., additional, Venturini, A., additional, Al-Shanti, N., additional, Stewart, C., additional, Ascione, R., additional, Angelini, G., additional, Suleiman, M.-S., additional, Kravchuk, E., additional, Grineva, E., additional, Galagudza, M., additional, Kostareva, A., additional, Bairamov, A., additional, Krychtiuk, K. A., additional, Watzke, L., additional, Kaun, C., additional, Demyanets, S., additional, Pisoni, J., additional, Kastl, S. P., additional, Huber, K., additional, Maurer, G., additional, Wojta, J., additional, Speidl, W. S., additional, Varga, Z. V., additional, Farago, N., additional, Zvara, A., additional, Kocsis, G. F., additional, Pipicz, M., additional, Csonka, C., additional, Csont, T., additional, Puskas, G. L., additional, Ferdinandy, P., additional, Klevstigova, M., additional, Silhavy, J., additional, Manakov, D., additional, Papousek, F., additional, Novotny, J., additional, Pravenec, M., additional, Kolar, F., additional, Novakova, O., additional, Novak, F., additional, Neckar, J., additional, Barallobre-Barreiro, J., additional, Didangelos, A., additional, Yin, X., additional, Fernandez-Caggiano, M., additional, Drozdov, I., additional, Willeit, P., additional, Domenech, N., additional, Mayr, M., additional, Lemoine, S., additional, Allouche, S., additional, Coulbault, L., additional, Galera, P., additional, Gerard, J. L., additional, Hanouz, J. L., additional, Suveren, E., additional, Whiteman, M., additional, Studneva, I. M., additional, Pisarenko, O., additional, Shulzhenko, V., additional, Serebryakova, L., additional, Tskitishvili, O., additional, Timoshin, A., additional, Fauconnier, J., additional, Meli, A. C., additional, Thireau, J., additional, Roberge, S., additional, Lompre, A. M., additional, Jacotot, E., additional, Marks, A. M., additional, Lacampagne, A., additional, Dietel, B., additional, Altendorf, R., additional, Daniel, W. G., additional, Kollmar, R., additional, Garlichs, C. D., additional, Parente, V., additional, Balasso, S., additional, Pompilio, G., additional, Colombo, G., additional, Milano, G., additional, Squadroni, L., additional, Cotelli, F., additional, Pozzoli, O., additional, Capogrossi, M. C., additional, Ajiro, Y., additional, Saegusa, N., additional, Iwade, K., additional, Giles, W. R., additional, Stafforini, D. M., additional, Spitzer, K. W., additional, Sirohi, R., additional, Candilio, L., additional, Babu, G., additional, Roberts, N., additional, Lawrence, D., additional, Sheikh, A., additional, Kolvekar, S., additional, Yap, J., additional, Hausenloy, D. J., additional, Yellon, D. M., additional, Aslam, M., additional, Rohrbach, S., additional, Schlueter, K.-D., additional, Piper, H. M., additional, Noll, T., additional, Guenduez, D., additional, Malinova, L., additional, Ryabukho, V. P., additional, Lyakin, D. V., additional, Denisova, T. P., additional, Montoro-Garcia, S., additional, Shantsila, E., additional, Lip, G. Y. H., additional, Kalaska, B., additional, Sokolowska, E., additional, Kaminski, K., additional, Szczubialka, K., additional, Kramkowski, K., additional, Mogielnicki, A., additional, Nowakowska, M., additional, Buczko, W., additional, Stancheva, N., additional, Mekenyan, E., additional, Gospodinov, K., additional, Tisheva, S., additional, Darago, A., additional, Rutkai, I., additional, Kalasz, J., additional, Czikora, A., additional, Orosz, P., additional, Bjornson, H. D., additional, Edes, I., additional, Papp, Z., additional, Toth, A., additional, Riches, K., additional, Warburton, P., additional, O'regan, D. J., additional, Ball, S. G., additional, Turner, N. A., additional, Wood, I. C., additional, Porter, K. E., additional, Kogaki, S., additional, Ishida, H., additional, Nawa, N., additional, Takahashi, K., additional, Baden, H., additional, Ichimori, H., additional, Uchikawa, T., additional, Mihara, S., additional, Miura, K., additional, Ozono, K., additional, Lugano, R., additional, Padro, T., additional, Garcia-Arguinzonis, M., additional, Badimon, L., additional, Ferraro, F., additional, Viner, R., additional, Ho, J., additional, Cutler, D., additional, Matchkov, V., additional, Aalkjaer, C., additional, Krijnen, P. A. J., additional, Hahn, N. E., additional, Kholova, I., additional, Sipkens, J. A., additional, Van Alphen, F. P., additional, Simsek, S., additional, Schalkwijk, C. G., additional, Van Buul, J. D., additional, Van Hinsbergh, V. W. M., additional, Niessen, H. W. M., additional, Caro, C. G., additional, Seneviratne, A., additional, Monaco, C., additional, Hou, D., additional, Singh, J., additional, Gilson, P., additional, Burke, M. G., additional, Heraty, K. B., additional, Krams, R., additional, Coppola, G., additional, Albrecht, K., additional, Schgoer, W., additional, Wiedemann, D., additional, Bonaros, N., additional, Steger, C., additional, Theurl, M., additional, Stanzl, U., additional, Kirchmair, R., additional, Amadesi, S., additional, Spinetti, G., additional, Cangiano, E., additional, Valgimigli, M., additional, Miller, A. M., additional, Cardinali, A., additional, Vierlinger, K., additional, Pagano, G., additional, Liccardo, D., additional, Zincarelli, C., additional, Femminella, G. D., additional, Lymperopoulos, A., additional, De Lucia, C., additional, Koch, W. J., additional, Leosco, D., additional, Rengo, G., additional, Hinkel, R., additional, Husada, W., additional, Trenkwalder, T., additional, Di, Q., additional, Lee, S., additional, Petersen, B., additional, Bock-Marquette, I., additional, Niemann, H., additional, Di Maio, M., additional, Kupatt, C., additional, Nourian, M., additional, Yassin, Z., additional, Kelishadi, R., additional, Memarian, S. H., additional, Heidari, A., additional, Leuner, A., additional, Poitz, D. M., additional, Brunssen, C., additional, Ravens, U., additional, Strasser, R. H., additional, Morawietz, H., additional, Vogt, F., additional, Grahl, A., additional, Flege, C., additional, Marx, N., additional, Borinski, M., additional, De Geest, B., additional, Jacobs, F., additional, Muthuramu, I., additional, Gordts, S. C., additional, Van Craeyveld, E., additional, Herijgers, P., additional, Weinert, S., additional, Medunjanin, S., additional, Herold, J., additional, Schmeisser, A., additional, Braun-Dullaeus, R. C., additional, Wagner, A. H., additional, Moeller, K., additional, Adolph, O., additional, Schwarz, M., additional, Schwale, C., additional, Bruehl, C., additional, Nobiling, R., additional, Wieland, T., additional, Schneider, S. W., additional, Hecker, M., additional, Cross, A., additional, Strom, A., additional, Cole, J., additional, Goddard, M., additional, Hultgardh-Nilsson, A., additional, Nilsson, J., additional, Mauri, C., additional, Mitkovskaya, N. P., additional, Kurak, T. A., additional, Oganova, E. G., additional, Shkrebneva, E. I., additional, Kot, Z. H. N., additional, Statkevich, T. V., additional, Molica, F., additional, Burger, F., additional, Matter, C. M., additional, Thomas, A., additional, Staub, C., additional, Zimmer, A., additional, Cravatt, B., additional, Pacher, P., additional, Steffens, S., additional, Blanco, R., additional, Sarmiento, R., additional, Parisi, C., additional, Fandino, S., additional, Blanco, F., additional, Gigena, G., additional, Szarfer, J., additional, Rodriguez, A., additional, Garcia Escudero, A., additional, Riccitelli, M. A., additional, Wantha, S., additional, Simsekyilmaz, S., additional, Megens, R. T., additional, Van Zandvoort, M. A., additional, Liehn, E., additional, Zernecke, A., additional, Klee, D., additional, Weber, C., additional, Soehnlein, O., additional, Lima, L. M., additional, Carvalho, M. G., additional, Gomes, K. B., additional, Santos, I. R., additional, Sousa, M. O., additional, Morais, C. A. S., additional, Oliveira, S. H. V., additional, Gomes, I. F., additional, Brandao, F. C., additional, Lamego, M. R. A., additional, Fornai, L., additional, Kiss, A., additional, Giskes, F., additional, Eijkel, G., additional, Fedrigo, M., additional, Valente, M. L., additional, Heeren, R. M. A., additional, Grdinic, A., additional, Vojvodic, D., additional, Djukanovic, N., additional, Grdinic, A. G., additional, Obradovic, S., additional, Majstorovic, I., additional, Rusovic, S., additional, Vucinic, Z., additional, Tavciovski, D., additional, Ostojic, M., additional, Lai, S.-C., additional, Chen, M.-Y., additional, Wu, H.-T., additional, Gouweleeuw, L., additional, Oberdorf-Maass, S. U., additional, De Boer, R. A., additional, Van Gilst, W. H., additional, Maass, A. H., additional, Van Gelder, I. C., additional, Benard, L., additional, Li, C., additional, Warren, D., additional, Shanahan, C. M., additional, Zhang, Q. P., additional, Bye, A., additional, Vettukattil, R., additional, Aspenes, S. T., additional, Giskeodegaard, G., additional, Gribbestad, I. S., additional, Wisloff, U., additional, Bathen, T. F., additional, Cubedo, J., additional, Alonso, R., additional, Mata, P., additional, Ivic, I., additional, Vamos, Z., additional, Cseplo, P., additional, Kosa, D., additional, Torok, O., additional, Hamar, J., additional, Koller, A., additional, Norita, K., additional, De Noronha, S. V., additional, Sheppard, M. N., additional, Amat-Roldan, I., additional, Iruretagoiena, I., additional, Psilodimitrakopoulos, S., additional, Crispi, F., additional, Artigas, D., additional, Loza-Alvarez, P., additional, Harrison, J. C., additional, Smart, S. D., additional, Besely, E. H., additional, Kelly, J. R., additional, Yao, Y., additional, Sammut, I. A., additional, Hoepfner, M., additional, Kuzyniak, W., additional, Sekhosana, E., additional, Hoffmann, B., additional, Litwinski, C., additional, Pries, A., additional, Ermilov, E., additional, Fontoura, D., additional, Lourenco, A. P., additional, Vasques-Novoa, F., additional, Pinto, J. 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Published
2012
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23. Transcriptional Regulation of Protein Synthesis by Mediator Kinase Represents a Therapeutic Vulnerability in MYC-driven Medulloblastoma.

Author

Wang D, Ritz C, Pierce A, Veo B, Luo Y, Brunt B, Dahl N, Suresh A, Serkova N, Venkataraman S, Danis E, Kuś K, Mazan M, Rzymski T, and Vibhakar R

Abstract

MYC-driven medulloblastoma (MB) is a highly aggressive cancer type with poor prognosis and limited treatment options. Through CRISPR-Cas9 screening of MB cell lines, we identified the Mediator-associated kinase CDK8 as a critical regulator of MYC-driven MB. Loss of CDK8 substantially reduces MYC expression, induces pronounced transcriptional changes, suppresses monosome assembly, and decreases ribosome biogenesis and protein synthesis, consequently inhibiting MB growth. Mechanistically, CDK8 regulates the occupancy of RNA polymerase II at specific chromatin loci, facilitating an epigenetic alteration that promotes the transcriptional regulation of ribosomal genes. Targeting CDK8 effectively diminishes the stem-like neoplastic cells characterized by hyperactive ribosome biogenesis. Furthermore, we demonstrated that the combined inhibition of CDK8 and mTOR synergizes to optimize therapeutic outcomes in vivo and in vivo . Overall, our findings establish a connection between CDK8-mediated transcriptional regulation and mRNA translation, suggesting a promising new therapeutic approach that targets the protein synthesis for MYC-driven MB., Competing Interests: Competing Interests DW, CR, BV, SV, ND, AP, BB, AS, NS, ED, YL, and RV report NO affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript. KK, MM and TR are employees of RVYU therapeutics.

Published
2024
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24. Inhibiting the MNK1/2-eIF4E axis impairs melanoma phenotype switching and potentiates antitumor immune responses.

Author

Huang F, Gonçalves C, Bartish M, Rémy-Sarrazin J, Issa ME, Cordeiro B, Guo Q, Emond A, Attias M, Yang W, Plourde D, Su J, Gimeno MG, Zhan Y, Galán A, Rzymski T, Mazan M, Masiejczyk M, Faber J, Khoury E, Benoit A, Gagnon N, Dankort D, Journe F, Ghanem GE, Krawczyk CM, Saragovi HU, Piccirillo CA, Sonenberg N, Topisirovic I, Rudd CE, Miller WH Jr, and Del Rincón SV

Published
2024
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26. Transcriptional Regulation of Protein Synthesis by Mediator Kinase in MYC-driven Medulloblastoma.

Author

Wang D, Ritz C, Pierce A, Brunt B, Luo Y, Dahl N, Venkataraman S, Danis E, Kuś K, Mazan M, Rzymski T, Veo B, and Vibhakar R

Abstract

MYC-driven medulloblastoma (MB) is a highly aggressive cancer type with poor prognosis and limited treatment options. Through CRISPR-Cas9 screening across MB cell lines, we identified the Mediator-associated kinase CDK8 as the top dependence for MYC-driven MB. Loss of CDK8 markedly reduces MYC expression and impedes MB growth. Mechanistically, we demonstrate that CDK8 depletion suppresses ribosome biogenesis and mRNA translation. CDK8 regulates occupancy of phospho-Polymerase II at specific chromatin loci facilitating an epigenetic alteration that promotes transcriptional regulation of ribosome biogenesis. Additionally, CDK8-mediated phosphorylation of 4EBP1 plays a crucial role in initiating eIF4E-dependent translation. Targeting CDK8 effectively suppresses cancer stem and progenitor cells, characterized by increased ribosome biogenesis activity. We also report the synergistic inhibition of CDK8 and mTOR in vivo and in vitro . Overall, our findings establish a connection between transcription and translation regulation, suggesting a promising therapeutic approach targets multiple points in the protein synthesis network for MYC-driven MB.

Published
2024
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27. Selective Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibition by the SCH772984 Compound Attenuates In Vitro and In Vivo Inflammatory Responses and Prolongs Survival in Murine Sepsis Models.

Author

Kopczynski M, Rumienczyk I, Kulecka M, Statkiewicz M, Pysniak K, Sandowska-Markiewicz Z, Wojcik-Trechcinska U, Goryca K, Pyziak K, Majewska E, Masiejczyk M, Wojcik-Jaszczynska K, Rzymski T, Bomsztyk K, Ostrowski J, and Mikula M

Subjects
Animals, Cell Line, Chemokine CCL2 blood, Disease Models, Animal, Down-Regulation drug effects, Drug Repositioning, Endotoxemia mortality, Gene Expression Regulation drug effects, Lipopolysaccharides toxicity, MAP Kinase Signaling System drug effects, Male, Mice, Mice, Inbred C57BL, Platelet Activation drug effects, RAW 264.7 Cells, Transcriptome genetics, Anti-Inflammatory Agents pharmacology, Endotoxemia drug therapy, Indazoles pharmacology, Mitogen-Activated Protein Kinase 3 antagonists & inhibitors, Piperazines pharmacology, Pyridines pharmacology, Pyrrolidines pharmacology, Triazoles pharmacology, Tumor Necrosis Factor-alpha biosynthesis
Abstract

Sepsis is the leading cause of death in intensive care units worldwide. Current treatments of sepsis are largely supportive and clinical trials using specific pharmacotherapy for sepsis have failed to improve outcomes. Here, we used the lipopolysaccharide (LPS)-stimulated mouse RAW264.7 cell line and AlphaLisa assay for TNFa as a readout to perform a supervised drug repurposing screen for sepsis treatment with compounds targeting epigenetic enzymes, including kinases. We identified the SCH772984 compound, an extracellular signal-regulated kinase (ERK) 1/2 inhibitor, as an effective blocker of TNFa production in vitro. RNA-Seq of the SCH772984-treated RAW264.7 cells at 1, 4, and 24 h time points of LPS challenge followed by functional annotation of differentially expressed genes highlighted the suppression of cellular pathways related to the immune system. SCH772984 treatment improved survival in the LPS-induced lethal endotoxemia and cecal ligation and puncture (CLP) mouse models of sepsis, and reduced plasma levels of Ccl2/Mcp1. Functional analyses of RNA-seq datasets for kidney, lung, liver, and heart tissues from SCH772984-treated animals collected at 6 h and 12 h post-CLP revealed a significant downregulation of pathways related to the immune response and platelets activation but upregulation of the extracellular matrix organization and retinoic acid signaling pathways. Thus, this study defined transcriptome signatures of SCH772984 action in vitro and in vivo, an agent that has the potential to improve sepsis outcome.

Published
2021
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28. Potential of enhancer of zeste homolog 2 inhibitors for the treatment of SWI/SNF mutant cancers and tumor microenvironment modulation.

Author

Pyziak K, Sroka-Porada A, Rzymski T, Dulak J, and Łoboda A

Subjects
Enzyme Inhibitors pharmacology, Humans, Polycomb Repressive Complex 2 genetics, Polycomb Repressive Complex 2 metabolism, Tumor Microenvironment, Enhancer of Zeste Homolog 2 Protein genetics, Enhancer of Zeste Homolog 2 Protein metabolism, Neoplasms drug therapy, Neoplasms genetics
Abstract

Enhancer of zeste homolog 2 (EZH2), a catalytic component of polycomb repressive complex 2 (PRC2), is commonly overexpressed or mutated in many cancer types, both of hematological and solid nature. Till now, plenty of EZH2 small molecule inhibitors have been developed and some of them have already been tested in clinical trials. Most of these inhibitors, however, are effective only in limited cases in the context of EZH2 gain-of-function mutated tumors such as lymphomas. Other cancer types with aberrant EZH2 expression and function require alternative approaches for successful treatment. One possibility is to exploit synthetic lethal strategy, which is based on the phenomenon that concurrent loss of two genes is detrimental but the deletion of either of them leaves cell viable. In the context of EZH2/PRC2, the most promising synthetic lethal target seems to be SWItch/Sucrose Non-Fermentable chromatin remodeling complex (SWI/SNF), which is known to counteract PRC2 functions. SWI/SNF is heavily involved in carcinogenesis and its subunits have been found mutated in approximately 20% of tumors of different kinds. In the current review, we summarize the existing knowledge of synthetic lethal relationships between EZH2/PRC2 and components of the SWI/SNF complex and discuss in detail the potential application of existing EZH2 inhibitors in cancer patients harboring mutations in SWI/SNF proteins. We also highlight recent discoveries of EZH2 involvement in tumor microenvironment regulation and consequences for future therapies. Although clinical studies are limited, the fundamental research might help to understand which patients are most likely to benefit from therapies using EZH2 inhibitors., (© 2021 Wiley Periodicals, LLC.)

Published
2021
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29. Inhibiting the MNK1/2-eIF4E axis impairs melanoma phenotype switching and potentiates antitumor immune responses.

Author

Huang F, Gonçalves C, Bartish M, Rémy-Sarrazin J, Issa ME, Cordeiro B, Guo Q, Emond A, Attias M, Yang W, Plourde D, Su J, Gimeno MG, Zhan Y, Galán A, Rzymski T, Mazan M, Masiejczyk M, Faber J, Khoury E, Benoit A, Gagnon N, Dankort D, Journe F, Ghanem GE, Krawczyk CM, Saragovi HU, Piccirillo CA, Sonenberg N, Topisirovic I, Rudd CE, Miller WH Jr, and Del Rincón SV

Subjects
Animals, B7-H1 Antigen genetics, B7-H1 Antigen immunology, Cell Line, Tumor, Eukaryotic Initiation Factor-4E genetics, Immunotherapy, MAP Kinase Signaling System genetics, Melanoma, Experimental genetics, Melanoma, Experimental therapy, Mice, Mice, Transgenic, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor genetics, Programmed Cell Death 1 Receptor immunology, Protein Serine-Threonine Kinases genetics, Receptor, Nerve Growth Factor genetics, Receptor, Nerve Growth Factor immunology, CD8-Positive T-Lymphocytes immunology, Eukaryotic Initiation Factor-4E immunology, Immunity, Cellular, MAP Kinase Signaling System immunology, Melanoma, Experimental immunology, Protein Serine-Threonine Kinases immunology
Abstract

Melanomas commonly undergo a phenotype switch, from a proliferative to an invasive state. Such tumor cell plasticity contributes to immunotherapy resistance; however, the mechanisms are not completely understood and thus are therapeutically unexploited. Using melanoma mouse models, we demonstrated that blocking the MNK1/2-eIF4E axis inhibited melanoma phenotype switching and sensitized melanoma to anti-PD-1 immunotherapy. We showed that phospho-eIF4E-deficient murine melanomas expressed high levels of melanocytic antigens, with similar results verified in patient melanomas. Mechanistically, we identified phospho-eIF4E-mediated translational control of NGFR, a critical effector of phenotype switching. Genetic ablation of phospho-eIF4E reprogrammed the immunosuppressive microenvironment, exemplified by lowered production of inflammatory factors, decreased PD-L1 expression on dendritic cells and myeloid-derived suppressor cells, and increased CD8+ T cell infiltrates. Finally, dual blockade of the MNK1/2-eIF4E axis and the PD-1/PD-L1 immune checkpoint demonstrated efficacy in multiple melanoma models regardless of their genomic classification. An increase in the presence of intratumoral stem-like TCF1+PD-1+CD8+ T cells, a characteristic essential for durable antitumor immunity, was detected in mice given a MNK1/2 inhibitor and anti-PD-1 therapy. Using MNK1/2 inhibitors to repress phospho-eIF4E thus offers a strategy to inhibit melanoma plasticity and improve response to anti-PD-1 immunotherapy.

Published
2021
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30. Discovery of indazole-pyridinone derivatives as a novel class of potent and selective MNK1/2 kinase inhibitors that protecting against endotoxin-induced septic shock.

Author

Dreas A, Kucwaj-Brysz K, Pyziak K, Kulesza U, Wincza E, Fabritius CH, Michalik K, Gabor-Worwa E, Gołas A, Milik M, Masiejczyk M, Majewska E, Pyśniak K, Wójcik-Trechcińska U, Sandowska-Markiewicz Z, Brzózka K, Ostrowski J, Rzymski T, and Mikula M

Subjects
Amino Acid Sequence, Animals, Cytokines metabolism, Dose-Response Relationship, Drug, Drug Discovery, Endotoxins metabolism, Eukaryotic Initiation Factor-4E metabolism, Humans, Immunologic Factors pharmacology, Mice, Molecular Docking Simulation, Protein Binding, Protein Kinase Inhibitors pharmacology, Shock, Septic chemically induced, Signal Transduction, Structure-Activity Relationship, Immunologic Factors chemical synthesis, Indazoles chemistry, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Protein Kinase Inhibitors chemical synthesis, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyridones chemistry, Shock, Septic drug therapy
Abstract

The mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (MNKs 1/2) and their downstream target eIF4E, play a role in oncogenic transformation, progression and metastasis. These results provided rationale for development of first MNKs inhibitors, currently in clinical trials for cancer treatment. Inhibitors of the MNKs/eIF4E pathway are also proposed as treatment strategy for inflammatory conditions. Here we present results of optimization of indazole-pyridinone derived MNK1/2 inhibitors among which compounds 24 and 26, selective and metabolically stable derivatives. Both compounds decreased levels of eIF4E Ser206 phosphorylation (pSer209-eIF4E) in MOLM16 cell line. When administered in mice compounds 24 and 26 significantly improved survival rates of animals in the endotoxin lethal dose challenge model, with concomitant reduction of proinflammatory cytokine levels - TNFα and IL-6 in serum. Identified MNK1/2 inhibitors represent a novel class of immunomodulatory compounds with a potential for the treatment of inflammatory diseases including sepsis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Published
2021
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31. Serine Biosynthesis Pathway Supports MYC-miR-494-EZH2 Feed-Forward Circuit Necessary to Maintain Metabolic and Epigenetic Reprogramming of Burkitt Lymphoma Cells.

Author

Białopiotrowicz E, Noyszewska-Kania M, Kachamakova-Trojanowska N, Łoboda A, Cybulska M, Grochowska A, Kopczyński M, Mikula M, Prochorec-Sobieszek M, Firczuk M, Graczyk-Jarzynka A, Zagożdżon R, Ząbek A, Młynarz P, Dulak J, Górniak P, Szydłowski M, Pyziak K, Martyka J, Sroka-Porada A, Jabłońska E, Polak A, Kowalczyk P, Szumera-Ciećkiewicz A, Chapuy B, Rzymski T, Brzózka K, and Juszczyński P

Abstract

Burkitt lymphoma (BL) is a rapidly growing tumor, characterized by high anabolic requirements. The MYC oncogene plays a central role in the pathogenesis of this malignancy, controlling genes involved in apoptosis, proliferation, and cellular metabolism. Serine biosynthesis pathway (SBP) couples glycolysis to folate and methionine cycles, supporting biosynthesis of certain amino acids, nucleotides, glutathione, and a methyl group donor, S-adenosylmethionine (SAM). We report that BLs overexpress SBP enzymes, phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). Both genes are controlled by the MYC-dependent ATF4 transcription factor. Genetic ablation of PHGDH/PSAT1 or chemical PHGDH inhibition with NCT-503 decreased BL cell lines proliferation and clonogenicity. NCT-503 reduced glutathione level, increased reactive oxygen species abundance, and induced apoptosis. Consistent with the role of SAM as a methyl donor, NCT-503 decreased DNA and histone methylation, and led to the re-expression of ID4 , KLF4 , CDKN2B and TXNIP tumor suppressors. High H3K27me3 level is known to repress the MYC negative regulator miR-494. NCT-503 decreased H3K27me3 abundance, increased the miR-494 level, and reduced the expression of MYC and MYC-dependent histone methyltransferase, EZH2. Surprisingly, chemical/genetic disruption of SBP did not delay BL and breast cancer xenografts growth, suggesting the existence of mechanisms compensating the PHGDH/PSAT1 absence in vivo., Competing Interests: P. Juszczynski is a member of the Scientific Advisory Board at Selvita S.A. and served as a consultant for Selvita S.A. Dr. T. Rzymski, Dr. K. Brzozka and P. Kowalczyk are Selvita S.A. employees.

Published
2020
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32. Inhibitory effects of SEL201 in acute myeloid leukemia.

Author

Kosciuczuk EM, Kar AK, Blyth GT, Fischietti M, Abedin S, Mina AA, Siliezar R, Rzymski T, Brzozka K, Eklund EA, Beauchamp EM, Eckerdt F, Saleiro D, and Platanias LC

Abstract

MAPK interacting kinase (MNK), a downstream effector of mitogen-activated protein kinase (MAPK) pathways, activates eukaryotic translation initiation factor 4E (eIF4E) and plays a key role in the mRNA translation of mitogenic and antiapoptotic genes in acute myeloid leukemia (AML) cells. We examined the antileukemic properties of a novel MNK inhibitor, SEL201. Our studies provide evidence that SEL201 suppresses eIF4E phosphorylation on Ser209 in AML cell lines and in primary patient-derived AML cells. Such effects lead to growth inhibitory effects and leukemic cell apoptosis, as well as suppression of leukemic progenitor colony formation. Combination of SEL201 with 5'-azacytidine or rapamycin results in synergistic inhibition of AML cell growth. Collectively, these results suggest that SEL201 has significant antileukemic activity and further underscore the relevance of the MNK pathway in leukemogenesis., Competing Interests: CONFLICTS OF INTEREST T. Rzymski, K. Brzozka are employees of Ryvu Therapeutics and stockholders of Ryvu Therapeutics/Selvita S.A. K. Brzozka is also a board member of Ryvu Therapeutics., (Copyright: © 2019 Kosciuczuk et al.)

Published
2019
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33. Synthesis of amide and sulfonamide substituted N-aryl 6-aminoquinoxalines as PFKFB3 inhibitors with improved physicochemical properties.

Author

Boutard N, Białas A, Sabiniarz A, Guzik P, Banaszak K, Biela A, Bień M, Buda A, Bugaj B, Cieluch E, Cierpich A, Dudek Ł, Eggenweiler HM, Fogt J, Gaik M, Gondela A, Jakubiec K, Jurzak M, Kitlińska A, Kowalczyk P, Kujawa M, Kwiecińska K, Leś M, Lindemann R, Maciuszek M, Mikulski M, Niedziejko P, Obara A, Pawlik H, Rzymski T, Sieprawska-Lupa M, Sowińska M, Szeremeta-Spisak J, Stachowicz A, Tomczyk MM, Wiklik K, Włoszczak Ł, Ziemiańska S, Zarębski A, Brzózka K, Nowak M, and Fabritius CH

Subjects
HCT116 Cells, Humans, Kinetics, Solubility, Amides chemistry, Phosphofructokinase-2 antagonists & inhibitors, Quinoxalines chemistry, Quinoxalines pharmacology, Sulfonamides chemistry
Abstract

In oncology, the "Warburg effect" describes the elevated production of energy by glycolysis in cancer cells. The ubiquitous and hypoxia-induced 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) plays a noteworthy role in the regulation of glycolysis by producing fructose-2,6-biphosphate (F-2,6-BP), a potent activator of the glycolysis rate-limiting phosphofructokinase PFK-1. Series of amides and sulfonamides derivatives based on a N-aryl 6-aminoquinoxaline scaffold were synthesized and tested for their inhibition of PFKFB3 in vitro in a biochemical assay as well as in HCT116 cells. The carboxamide series displayed satisfactory kinetic solubility and metabolic stability, and within this class, potent lead compounds with low nanomolar activity have been identified with a suitable profile for further in vivo evaluation., (Copyright © 2018. Published by Elsevier Ltd.)

Published
2019
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34. Discovery and Structure-Activity Relationships of N-Aryl 6-Aminoquinoxalines as Potent PFKFB3 Kinase Inhibitors.

Author

Boutard N, Białas A, Sabiniarz A, Guzik P, Banaszak K, Biela A, Bień M, Buda A, Bugaj B, Cieluch E, Cierpich A, Dudek Ł, Eggenweiler HM, Fogt J, Gaik M, Gondela A, Jakubiec K, Jurzak M, Kitlińska A, Kowalczyk P, Kujawa M, Kwiecińska K, Leś M, Lindemann R, Maciuszek M, Mikulski M, Niedziejko P, Obara A, Pawlik H, Rzymski T, Sieprawska-Lupa M, Sowińska M, Szeremeta-Spisak J, Stachowicz A, Tomczyk MM, Wiklik K, Włoszczak Ł, Ziemiańska S, Zarębski A, Brzózka K, Nowak M, and Fabritius CH

Subjects
Cell Survival drug effects, Crystallography, X-Ray, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, HCT116 Cells, Humans, Lactic Acid antagonists & inhibitors, Lactic Acid biosynthesis, Models, Molecular, Molecular Structure, Phosphofructokinase-2 metabolism, Quinoxalines chemical synthesis, Structure-Activity Relationship, Drug Discovery, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Phosphofructokinase-2 antagonists & inhibitors, Quinoxalines chemistry, Quinoxalines pharmacology
Abstract

Energy and biomass production in cancer cells are largely supported by aerobic glycolysis in what is called the Warburg effect. The process is regulated by key enzymes, among which phosphofructokinase PFK-2 plays a significant role by producing fructose-2,6-biphosphate; the most potent activator of the glycolysis rate-limiting step performed by phosphofructokinase PFK-1. Herein, the synthesis, biological evaluation and structure-activity relationship of novel inhibitors of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), which is the ubiquitous and hypoxia-induced isoform of PFK-2, are reported. X-ray crystallography and docking were instrumental in the design and optimisation of a series of N-aryl 6-aminoquinoxalines. The most potent representative, N-(4-methanesulfonylpyridin-3-yl)-8-(3-methyl-1-benzothiophen-5-yl)quinoxalin-6-amine, displayed an IC 50 of 14 nm for the target and an IC 50 of 0.49 μm for fructose-2,6-biphosphate production in human colon carcinoma HCT116 cells. This work provides a new entry in the field of PFKFB3 inhibitors with potential for development in oncology., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Published
2019
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35. MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma.

Author

Zhan Y, Guo J, Yang W, Goncalves C, Rzymski T, Dreas A, Żyłkiewicz E, Mikulski M, Brzózka K, Golas A, Kong Y, Ma M, Huang F, Huor B, Guo Q, da Silva SD, Torres J, Cai Y, Topisirovic I, Su J, Bijian K, Alaoui-Jamali MA, Huang S, Journe F, Ghanem GE, Miller WH Jr, and Del Rincón SV

Subjects
Animals, Cell Line, Tumor, Female, Humans, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Intracellular Signaling Peptides and Proteins metabolism, Male, Melanoma enzymology, Melanoma secondary, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, SCID, Mutation, Missense, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Mas, Proto-Oncogene Proteins c-kit genetics, Signal Transduction, Skin Neoplasms enzymology, Skin Neoplasms pathology, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Dasatinib pharmacology, Melanoma drug therapy, Skin Neoplasms drug therapy
Abstract

Melanoma can be stratified into unique subtypes based on distinct pathologies. The acral/mucosal melanoma subtype is characterized by aberrant and constitutive activation of the proto-oncogene receptor tyrosine kinase C-KIT, which drives tumorigenesis. Treatment of these melanoma patients with C-KIT inhibitors has proven challenging, prompting us to investigate the downstream effectors of the C-KIT receptor. We determined that C-KIT stimulates MAP kinase-interacting serine/threonine kinases 1 and 2 (MNK1/2), which phosphorylate eukaryotic translation initiation factor 4E (eIF4E) and render it oncogenic. Depletion of MNK1/2 in melanoma cells with oncogenic C-KIT inhibited cell migration and mRNA translation of the transcriptional repressor SNAI1 and the cell cycle gene CCNE1. This suggested that blocking MNK1/2 activity may inhibit tumor progression, at least in part, by blocking translation initiation of mRNAs encoding cell migration proteins. Moreover, we developed an MNK1/2 inhibitor (SEL201), and found that SEL201-treated KIT-mutant melanoma cells had lower oncogenicity and reduced metastatic ability. Clinically, tumors from melanoma patients harboring KIT mutations displayed a marked increase in MNK1 and phospho-eIF4E. Thus, our studies indicate that blocking MNK1/2 exerts potent antimelanoma effects and support blocking MNK1/2 as a potential strategy to treat patients positive for KIT mutations.

Published
2017
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36. SEL120-34A is a novel CDK8 inhibitor active in AML cells with high levels of serine phosphorylation of STAT1 and STAT5 transactivation domains.

Author

Rzymski T, Mikula M, Żyłkiewicz E, Dreas A, Wiklik K, Gołas A, Wójcik K, Masiejczyk M, Wróbel A, Dolata I, Kitlińska A, Statkiewicz M, Kuklinska U, Goryca K, Sapała Ł, Grochowska A, Cabaj A, Szajewska-Skuta M, Gabor-Worwa E, Kucwaj K, Białas A, Radzimierski A, Combik M, Woyciechowski J, Mikulski M, Windak R, Ostrowski J, and Brzózka K

Subjects
Animals, Antineoplastic Agents chemistry, Cell Line, Tumor, Cyclin-Dependent Kinase 8 chemistry, Disease Models, Animal, Gene Expression Profiling, Gene Expression Regulation, Leukemic drug effects, Humans, Leukemia, Myeloid, Acute genetics, Mice, Models, Molecular, Molecular Conformation, Phosphorylation drug effects, Protein Binding, Protein Kinase Inhibitors chemistry, STAT1 Transcription Factor chemistry, STAT5 Transcription Factor chemistry, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Cyclin-Dependent Kinase 8 antagonists & inhibitors, Leukemia, Myeloid, Acute metabolism, Protein Interaction Domains and Motifs drug effects, Protein Kinase Inhibitors pharmacology, STAT1 Transcription Factor metabolism, STAT5 Transcription Factor metabolism
Abstract

Inhibition of oncogenic transcriptional programs is a promising therapeutic strategy. A substituted tricyclic benzimidazole, SEL120-34A, is a novel inhibitor of Cyclin-dependent kinase 8 (CDK8), which regulates transcription by associating with the Mediator complex. X-ray crystallography has shown SEL120-34A to be a type I inhibitor forming halogen bonds with the protein's hinge region and hydrophobic complementarities within its front pocket. SEL120-34A inhibits phosphorylation of STAT1 S727 and STAT5 S726 in cancer cells in vitro. Consistently, regulation of STATs- and NUP98-HOXA9- dependent transcription has been observed as a dominant mechanism of action in vivo. Treatment with the compound resulted in a differential efficacy on AML cells with elevated STAT5 S726 levels and stem cell characteristics. In contrast, resistant cells were negative for activated STAT5 and revealed lineage commitment. In vivo efficacy in xenotransplanted AML models correlated with significant repression of STAT5 S726. Favorable pharmacokinetics, confirmed safety and in vivo efficacy provide a rationale for the further clinical development of SEL120-34A as a personalized therapeutic approach in AML.

Published
2017
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37. Mitogen-activated Protein Kinase (MAPK) Interacting Kinases 1 and 2 (MNK1 and MNK2) as Targets for Cancer Therapy: Recent Progress in the Development of MNK Inhibitors.

Author

Dreas A, Mikulski M, Milik M, Fabritius CH, Brzózka K, and Rzymski T

Subjects
Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Fusion Proteins, bcr-abl antagonists & inhibitors, Humans, Intracellular Signaling Peptides and Proteins chemistry, Molecular Targeted Therapy, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors therapeutic use, Protein Serine-Threonine Kinases chemistry, Signal Transduction, Antineoplastic Agents pharmacology, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors
Abstract

MAP kinase-interacting kinases (MNK1 and MNK2) are often activated downstream of ERK and p38 MAPK in the MAP kinase family. The role of MNKs in the development and progression of solid tumors and hematological malignancies has been widely discussed, particularly in the context of cap dependent translation, regulated by phosphorylation of eIF4E. MNK/eIF4E axis is involved in the expression of pro angiogenic, antiapoptotic, cell cycle, and motility proteins, such as MCL1, VEGF, MMP3, SNAIL, SMAD2, β-catenin or cyclin D1, and is essential during Ras and c Myc-induced transformation. MNK1/2 emerged as eligible targets for drug discovery in oncology, based on the antitumor effects observed in genetic knockout and RNA interference experiments and at the same time lack of adverse effects in dual knockout animals. There is a high interest in the development of pharmacological inhibitors of MNK1/2 as not only tools for further basic research studies but also potential drugs in diseases characterized by deregulated translation. Unfortunately, the role of MNK1/2 in cancer still remains elusive due to the absence of potent and selective probes. Moreover, in many instances, hypotheses have been built reliant upon unspecific MNK1/2 inhibitors such as CGP57380 or cercosporamide. Lately, the first two clinical programs targeting MNKs in oncology have been revealed (eFT508 and BAY 1143269), although several other MNK programs are currently running at the preclinical stage. This review aims to provide an overview of recent progress in the development of MNK inhibitors., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Published
2017
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38. CDK8 kinase--An emerging target in targeted cancer therapy.

Author

Rzymski T, Mikula M, Wiklik K, and Brzózka K

Subjects
Cyclin-Dependent Kinase 8 genetics, Gene Expression Regulation, Neoplastic drug effects, Humans, Molecular Structure, Neoplasms genetics, Niacinamide analogs & derivatives, Niacinamide chemistry, Niacinamide therapeutic use, Phenylurea Compounds chemistry, Phenylurea Compounds therapeutic use, Protein Conformation, Protein Kinase Inhibitors chemistry, Signal Transduction drug effects, Sorafenib, Cyclin-Dependent Kinase 8 antagonists & inhibitors, Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use, Transcription, Genetic drug effects
Abstract

Cyclin-dependent kinase (CDK) inhibitors have been developed as potential anticancer therapeutics and several nonselective compounds are currently in advanced clinical trials. This review is focused on the key biological roles of CDK8 kinase, which provide a proof-of-principle for continued efforts toward effective cancer treatment, targeting activity of this CDK family member. Among currently identified kinase inhibitors, several displayed significant selectivity for CDK8 and notably the effectiveness in targeting cancer specific gene expression programs. Structural features of CDK8 and available ligands were discussed from a perspective of the rational drug design process. Current state of the art confirms that further development of CDK8 inhibitors will translate into targeted therapies in oncology. This article is part of a Special Issue entitled:Inhibitors of Protein Kinases., (Copyright © 2015. Published by Elsevier B.V.)

Published
2015
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39. Role of ATF4 in regulation of autophagy and resistance to drugs and hypoxia.

Author

Rzymski T, Milani M, Singleton DC, and Harris AL

Subjects
Activating Transcription Factor 4 genetics, Cell Hypoxia, Drug Resistance, Neoplasm, Endoplasmic Reticulum drug effects, Humans, Unfolded Protein Response, eIF-2 Kinase metabolism, Activating Transcription Factor 4 physiology, Autophagy, Neoplasms metabolism
Abstract

Tumor hypoxia confers resistance to many modalities of anticancer therapy. The endoplasmic reticulum (ER) is highly sensitive to severe hypoxic stress and results in the activation of the unfolded protein response. ATF4 is the main transcriptional regulator of the cellular hypoxic response to the Unfolded Protein Response (UPR) and activates genes that promote restoration of normal ER function and survival under hypoxia. Elevated expression of ATF4 is associated with resistance to current chemotherapeutic drugs including DNA-interactive and damaging agents, nonsteroidal anti-inflammatory drugs and proteasome inhibitors. ATF4 decreases the antitumor activity of chemotherapy by mechanisms involving expression of genes involved in oxidative stress resistance, redox homeostasis and inhibitors of apoptosis. ATF4 plays also a crucial role in resistance to proteasomal inhibitor bortezomib (PS-341) by the induction of prosurvival pathways, such as autophagy, that can relieve the protein overload in bortezomib treated cells. Inhibition of ATF4 represents an attractive stand-alone therapy as well as an opportunity to enhance the efficacy of current chemotherapeutic agents without causing high tissue toxicity to normal tissues.

Published
2009
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40. Hypoxic activation of the unfolded protein response (UPR) induces expression of the metastasis-associated gene LAMP3.

Author

Mujcic H, Rzymski T, Rouschop KM, Koritzinsky M, Milani M, Harris AL, and Wouters BG

Subjects
Animals, Blotting, Western, Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Humans, Hypoxia metabolism, Immunohistochemistry, Lysosomal Membrane Proteins genetics, Mice, Mice, Inbred BALB C, Neoplasm Metastasis genetics, Neoplasm Proteins genetics, Polymerase Chain Reaction, Probability, Protein Array Analysis, RNA, Small Interfering analysis, Reference Values, Transfection, Tumor Cells, Cultured, Biomarkers, Tumor genetics, Hypoxia genetics, Lysosomal Membrane Proteins metabolism, Neoplasm Proteins metabolism, Unfolded Protein Response genetics
Abstract

Background and Purpose: Tumour hypoxia contributes to failure of cancer treatment through its ability to protect against therapy and adversely influence tumour biology. In particular, several studies suggest that hypoxia promotes metastasis. Hypoxia-induced cellular changes are mediated by oxygen-sensitive signaling pathways that activate downstream transcription factors. We have investigated the induction and transcriptional regulation of a novel metastasis-associated gene, LAMP3 during hypoxia., Materials and Methods: Microarray, quantitative PCR, Western blot analysis and immunohistochemistry were used to investigate hypoxic regulation of LAMP3. The mechanism for LAMP3 induction was investigated using transient RNAi and stable shRNA targeting components of the hypoxic response. Endoplasmic reticulum stress inducing agents, including proteasome inhibitors were assessed for their ability to regulate LAMP3., Results: LAMP3 is strongly induced by hypoxia at both the mRNA and protein levels in a large panel of human tumour cell lines. Induction of LAMP3 occurs as a consequence of the activation of the PERK/eIF2alpha/ATF4 arm of the unfolded protein response (UPR) and is independent of HIF-1alpha. LAMP3 is expressed heterogeneously within the microenvironment of tumours, overexpressed in breast cancer, and increases in tumours treated with avastin., Conclusions: These data identify LAMP3 as a novel hypoxia-inducible gene regulated by the UPR. LAMP3 is a new candidate biomarker of UPR activation by hypoxia in tumours and is a potential mediator of hypoxia-induced metastasis.

Published
2009
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41. The role of ATF4 stabilization and autophagy in resistance of breast cancer cells treated with Bortezomib.

Author

Milani M, Rzymski T, Mellor HR, Pike L, Bottini A, Generali D, and Harris AL

Subjects
Activating Transcription Factor 4 drug effects, Activating Transcription Factor 4 genetics, Bortezomib, Breast Neoplasms drug therapy, Cell Division drug effects, Cell Line, Tumor, Female, Flow Cytometry, Humans, Immunohistochemistry, Neoplasm Proteins drug effects, Neoplasm Proteins metabolism, Polymerase Chain Reaction, RNA, Neoplasm drug effects, RNA, Neoplasm genetics, RNA, Small Interfering drug effects, RNA, Small Interfering genetics, Activating Transcription Factor 4 metabolism, Antineoplastic Agents therapeutic use, Autophagy drug effects, Boronic Acids therapeutic use, Pyrazines therapeutic use
Abstract

The ubiquitin-proteasome system plays a key regulatory role in cellular homeostasis. The inhibition of the 26S proteasome by Bortezomib leads to the accumulation of misfolded proteins, resulting in endoplasmic reticulum stress followed by a coordinated cellular response called unfolded protein response (UPR). Endoplasmic reticulum stress is also a potent inducer of macroautophagy. Bortezomib is a selective and potent inhibitor of the 26S proteasome and is approved for the treatment of multiple myeloma. Clinical trials with Bortezomib have shown promising results for some types of cancers, but not for some others, including those of the breast. In this study, we show that Bortezomib induces the UPR and autophagy in MCF7 breast cancer cells. Surprisingly, Bortezomib did not induce phosphorylation of PERK, a key initial step of the UPR. We show that induction of autophagy by Bortezomib is dependent on the proteasomal stabilisation of ATF4 and up-regulation of LC3B by ATF4. We show that ATF4 and LC3B play a critical role in activating autophagy and protecting cells from Bortezomib-induced cell death. Our experiments also reveal that HDAC6 knockdown results in decreased LC3B protein and reduced autophagy. Our work shows that the induction of autophagy through ATF4 may be an important resistance mechanism to Bortezomib treatment in breast cancer, and targeting autophagy may represent a novel approach to sensitize breast cancers to Bortezomib.

Published
2009
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42. The unfolded protein response and integrated stress response to anoxia.

Author

Rzymski T and Harris AL

Subjects
Activating Transcription Factor 4 metabolism, Endoplasmic Reticulum enzymology, Humans, Hypoxia genetics, Neoplasm Proteins genetics, Neoplasms genetics, Protein Folding, Transcription, Genetic, eIF-2 Kinase metabolism, Hypoxia metabolism, Neoplasm Proteins metabolism, Neoplasms metabolism, Neoplasms pathology, Protein Biosynthesis
Abstract

The lack of oxygen delivery to tumor cells has profound consequences for tumor growth and correlates with poor prognosis. Some tumors contain regions of very severe hypoxia called anoxia, which constitutes a functionally different state to hypoxia. In response to anoxia, mammalian cells induce coordinated cytoprotective programs that are critical for tumor survival: the unfolded protein response and integrated stress response. Therefore, targeting additional components of anoxic pathways, besides the hypoxia-inducible response, may be effective for future anticancer therapies.

Published
2007
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43. ADAM family genes testase 2alpha and 2beta are chromosomally linked and simultaneously expressed in male germ cells.

Author

Bolcun E, Rzymski T, Nayernia K, and Engel W

Subjects
Animals, Male, Mice, Organ Specificity, Testis, Genetic Linkage, Spermatozoa enzymology
Abstract

The ADAM (a disintegrin and a metalloprotease) family includes the best-characterized proteins involved in gamete interaction and membrane fusion in mammals. Previous studies have shown that the murine testase 2 (ADAM 25) gene is expressed specifically in testis. We found two different restriction patterns of subcloned fragments of the gene, indicating the presence of two different testase 2 transcripts. Further experiments and Celera database searches demonstrated that the two transcripts are the products of two testase 2 genes, which are located on mouse chromosome 8 in close distance of 24 kb. They show high sequence similarity to the published testase 2 gene (87.8 and 95.5%, respectively). The genomic structure of both testase 2 genes (alpha and beta) is different from other ADAM family genes like that for cyritestin and fertilin. While these genes are composed of about 20 exons, the testase 2alpha and 2beta genes contain only two exons. The first exon is very short approximately 85 bp while the second exon is approximately 2.4 kb long. Both testase 2 genes are specifically expressed in testis and they exhibit the same temporal and spatial expression pattern during male germ cell differentiation with the onset of expression in haploid stages., (Copyright 2003 Wiley-Liss, Inc.)

Published
2003
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