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73 results on '"KIEFER, James R."'

51. An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells

Author

Vinogradova, Maia, primary, Gehling, Victor S, additional, Gustafson, Amy, additional, Arora, Shilpi, additional, Tindell, Charles A, additional, Wilson, Catherine, additional, Williamson, Kaylyn E, additional, Guler, Gulfem D, additional, Gangurde, Pranoti, additional, Manieri, Wanda, additional, Busby, Jennifer, additional, Flynn, E Megan, additional, Lan, Fei, additional, Kim, Hyo-jin, additional, Odate, Shobu, additional, Cochran, Andrea G, additional, Liu, Yichin, additional, Wongchenko, Matthew, additional, Yang, Yibin, additional, Cheung, Tommy K, additional, Maile, Tobias M, additional, Lau, Ted, additional, Costa, Michael, additional, Hegde, Ganapati V, additional, Jackson, Erica, additional, Pitti, Robert, additional, Arnott, David, additional, Bailey, Christopher, additional, Bellon, Steve, additional, Cummings, Richard T, additional, Albrecht, Brian K, additional, Harmange, Jean-Christophe, additional, Kiefer, James R, additional, Trojer, Patrick, additional, and Classon, Marie, additional

Published
2016
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52. Design and Development of a Series of Potent and Selective Type II Inhibitors of CDK8

Author

Bergeron, Philippe, primary, Koehler, Michael F. T., additional, Blackwood, Elizabeth M., additional, Bowman, Krista, additional, Clark, Kevin, additional, Firestein, Ron, additional, Kiefer, James R., additional, Maskos, Klaus, additional, McCleland, Mark L., additional, Orren, Linda, additional, Ramaswamy, Sreemathy, additional, Salphati, Laurent, additional, Schmidt, Steve, additional, Schneider, Elisabeth V., additional, Wu, Jiansheng, additional, and Beresini, Maureen, additional

Published
2016
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53. Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637)

Author

Taylor, Alexander M., primary, Côté, Alexandre, additional, Hewitt, Michael C., additional, Pastor, Richard, additional, Leblanc, Yves, additional, Nasveschuk, Christopher G., additional, Romero, F. Anthony, additional, Crawford, Terry D., additional, Cantone, Nico, additional, Jayaram, Hariharan, additional, Setser, Jeremy, additional, Murray, Jeremy, additional, Beresini, Maureen H., additional, de Leon Boenig, Gladys, additional, Chen, Zhongguo, additional, Conery, Andrew R., additional, Cummings, Richard T., additional, Dakin, Leslie A., additional, Flynn, E. Megan, additional, Huang, Oscar W., additional, Kaufman, Susan, additional, Keller, Patricia J., additional, Kiefer, James R., additional, Lai, Tommy, additional, Li, Yingjie, additional, Liao, Jiangpeng, additional, Liu, Wenfeng, additional, Lu, Henry, additional, Pardo, Eneida, additional, Tsui, Vickie, additional, Wang, Jian, additional, Wang, Yongyun, additional, Xu, Zhaowu, additional, Yan, Fen, additional, Yu, Dong, additional, Zawadzke, Laura, additional, Zhu, Xiaoqin, additional, Zhu, Xiaoyu, additional, Sims, Robert J., additional, Cochran, Andrea G., additional, Bellon, Steve, additional, Audia, James E., additional, Magnuson, Steven, additional, and Albrecht, Brian K., additional

Published
2016
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55. Development of a Potent, Specific CDK8 Kinase Inhibitor Which Phenocopies CDK8/19 Knockout Cells

Author

Koehler, Michael F. T., primary, Bergeron, Philippe, additional, Blackwood, Elizabeth M., additional, Bowman, Krista, additional, Clark, Kevin R., additional, Firestein, Ron, additional, Kiefer, James R., additional, Maskos, Klaus, additional, McCleland, Mark L., additional, Orren, Linda, additional, Salphati, Laurent, additional, Schmidt, Steve, additional, Schneider, Elisabeth V., additional, Wu, Jiansheng, additional, and Beresini, Maureen H., additional

Published
2016
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59. Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action

Author

René, Olivier, primary, Fauber, Benjamin P., additional, Boenig, Gladys de Leon, additional, Burton, Brenda, additional, Eidenschenk, Céline, additional, Everett, Christine, additional, Gobbi, Alberto, additional, Hymowitz, Sarah G., additional, Johnson, Adam R., additional, Kiefer, James R., additional, Liimatta, Marya, additional, Lockey, Peter, additional, Norman, Maxine, additional, Ouyang, Wenjun, additional, Wallweber, Heidi A., additional, and Wong, Harvey, additional

Published
2014
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61. Structure of human ADAM-8 catalytic domain complexed with batimastat

Author

Hall, Troii, primary, Shieh, Huey-Sheng, additional, Day, Jacqueline E., additional, Caspers, Nicole, additional, Chrencik, Jill E., additional, Williams, Jennifer M., additional, Pegg, Lyle E., additional, Pauley, Adele M., additional, Moon, Andrea F., additional, Krahn, Joseph M., additional, Fischer, David H., additional, Kiefer, James R., additional, Tomasselli, Alfredo G., additional, and Zack, Marc D., additional

Published
2012
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63. Orally Active MMP-1 Sparing α-Tetrahydropyranyl and α-Piperidinyl Sulfone Matrix Metalloproteinase (MMP) Inhibitors with Efficacy in Cancer, Arthritis, and Cardiovascular Disease

Author

Becker, Daniel P., primary, Barta, Thomas E., additional, Bedell, Louis J., additional, Boehm, Terri L., additional, Bond, Brian R., additional, Carroll, Jeffery, additional, Carron, Chris P., additional, DeCrescenzo, Gary A., additional, Easton, Alan M., additional, Freskos, John N., additional, Funckes-Shippy, Chris L., additional, Heron, Marcia, additional, Hockerman, Susan, additional, Howard, Carol Pearcy, additional, Kiefer, James R., additional, Li, Madeleine H., additional, Mathis, Karl J., additional, McDonald, Joseph J., additional, Mehta, Pramod P., additional, Munie, Grace E., additional, Sunyer, Teresa, additional, Swearingen, Craig A., additional, Villamil, Clara I., additional, Welsch, Dean, additional, Williams, Jennifer M., additional, Yu, Ying, additional, and Yao, Jun, additional

Published
2010
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64. Discovery of an Oral Potent Selective Inhibitor of Hematopoietic Prostaglandin D Synthase (HPGDS)

Author

Carron, Chris P., primary, Trujillo, John I., additional, Olson, Kirk L., additional, Huang, Wei, additional, Hamper, Bruce C., additional, Dice, Tom, additional, Neal, Bradley E., additional, Pelc, Matthew J., additional, Day, Jacqueline E., additional, Rohrer, Douglas C., additional, Kiefer, James R., additional, Moon, Joseph B., additional, Schweitzer, Barbara A., additional, Blake, Tanisha D., additional, Turner, Steve R., additional, Woerndle, Rhonda, additional, Case, Brenda L., additional, Bono, Christine P., additional, Dilworth, Vickie M., additional, Funckes-Shippy, Christie L., additional, Hood, Becky L., additional, Jerome, Gina M., additional, Kornmeier, Christine M., additional, Radabaugh, Melissa R., additional, Williams, Melanie L., additional, Davies, Michael S., additional, Wegner, Craig D., additional, Welsch, Dean J., additional, Abraham, William M., additional, Warren, Chad J., additional, Dowty, Martin E., additional, Hua, Fengmei, additional, Zutshi, Anup, additional, Yang, Jerry Z., additional, and Thorarensen, Atli, additional

Published
2010
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65. 2-(6-Phenyl-1H-indazol-3-yl)-1H-benzo[d]imidazoles: Design and synthesis of a potent and isoform selective PKC-ζ inhibitor

Author

Trujillo, John I., primary, Kiefer, James R., additional, Huang, Wei, additional, Thorarensen, Atli, additional, Xing, Li, additional, Caspers, Nicole L., additional, Day, Jacqueline E., additional, Mathis, Karl J., additional, Kretzmer, Kuniko K., additional, Reitz, Beverley A., additional, Weinberg, Robin A., additional, Stegeman, Roderick A., additional, Wrightstone, Ann, additional, Christine, Lori, additional, Compton, Robert, additional, and Li, Xiong, additional

Published
2009
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68. A proposed three step mechanism for inhibition of cyclooxygenase-2

Author

Walker, Mark C., primary, Kurumbail, Ravi G., additional, Hood, William F., additional, Monahan, Joseph B., additional, Pawlitz, Jennifer L., additional, Stegeman, Roderick A., additional, Stevens, Anna M., additional, Kiefer, James R., additional, Koboldt, Carol M., additional, Moreland, Kirby T., additional, Rowlinson, Scott, additional, Mamett, Lawrence J., additional, Pierce, Jennifer L., additional, Carter, Jeffery S., additional, Talley, John J., additional, Isakson, Peter C., additional, Seibert, Karen, additional, and Gierse, James K., additional

Published
1999
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69. Crystal structures of cyclooxygenase-2 variants with diarylheterocycle inhibitors: Contribution of the side pocket for selectivity

Author

Kurumbail, Ravi G., primary, Pawlitz, Jennifer L., additional, Kiefer, James R., additional, Stegeman, Roderick A., additional, Stevens, Anna M., additional, Gierse, James K., additional, Moreland, Kirby T., additional, Walker, Mark C., additional, Rowlinson, Scott W., additional, Marnett, Lawrence J., additional, and Stallings, William C., additional

Published
1999
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72. Target 2035 - update on the quest for a probe for every protein.

Author

Müller S, Ackloo S, Al Chawaf A, Al-Lazikani B, Antolin A, Baell JB, Beck H, Beedie S, Betz UAK, Bezerra GA, Brennan PE, Brown D, Brown PJ, Bullock AN, Carter AJ, Chaikuad A, Chaineau M, Ciulli A, Collins I, Dreher J, Drewry D, Edfeldt K, Edwards AM, Egner U, Frye SV, Fuchs SM, Hall MD, Hartung IV, Hillisch A, Hitchcock SH, Homan E, Kannan N, Kiefer JR, Knapp S, Kostic M, Kubicek S, Leach AR, Lindemann S, Marsden BD, Matsui H, Meier JL, Merk D, Michel M, Morgan MR, Mueller-Fahrnow A, Owen DR, Perry BG, Rosenberg SH, Saikatendu KS, Schapira M, Scholten C, Sharma S, Simeonov A, Sundström M, Superti-Furga G, Todd MH, Tredup C, Vedadi M, von Delft F, Willson TM, Winter GE, Workman P, and Arrowsmith CH

Abstract

Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function. Accordingly, a subset of human proteins has been at the heart of research interests of scientists over the centuries, and we have accumulated varying degrees of knowledge about approximately 65% of the human proteome. Nevertheless, a large proportion of proteins in the human proteome (∼35%) remains uncharacterized, and less than 5% of the human proteome has been successfully targeted for drug discovery. This highlights the profound disconnect between our abilities to obtain genetic information and subsequent development of effective medicines. Target 2035 is an international federation of biomedical scientists from the public and private sectors, which aims to address this gap by developing and applying new technologies to create by year 2035 chemogenomic libraries, chemical probes, and/or biological probes for the entire human proteome., Competing Interests: A. A. A., B. A.-L., I. C., and P. W. are employees of the Institute of Cancer Research (ICR) which operates a Rewards to Inventors scheme whereby employees of the ICR may receive financial benefit following commercial licensing of their research. P. W. is a consultant/scientific advisory board member for Nextech Invest Ltd, Storm Therapeutics, Astex Pharmaceuticals, Black Diamond Therapeutics, CV6 and Vividion Therapeutics, and holds stock in Chroma Therapeutics, NextInvest, and Storm Therapeutics. P. W. is also a non-executive director of Storm Therapeutics and the Royal Marsden NHS Trust; a board member and executive director of the non-profit Chemical Probes Portal; and a former employee of AstraZeneca. P. W. has received research funding from Vernalis, Astex Therapeutics, Merck KGaA, BACIT/Sixth Element Capital/CRT Pioneer Fund. B. A.-L. is/was a consultant/scientific advisory board member for GSK, Open Targets, Astex Pharmaceuticals, Nuvectis Pharma and Astellas Pharma, and is an ex-employee of Inpharmatica Ltd. A. A. A., B. A.-L., and P. W. have been instrumental in the creation/development of canSAR and Probe Miner. B. A.-L. was instrumental in the creation of ChEMBL and is a director of the non-profit Chemical Probes Portal. I. C. is/was a consultant to Epidarex LLP, AdoRx Therapeutics, and Enterprise Therapeutics, and is a director of the non-profit Chemical Probes Portal. I. C. has received research funding from Astex, Merck KGaA, Janssen Biopharma, Monte Rosa Therapeutics, and Sixth Element Capital/CRT Pioneer Fund. I. C. holds stock in Monte Rosa Therapeutics AG and is a former employee of Merck Sharp & Dohme. M. K. is a paid consultant for Life Science Editors (LSE). A. C. receives or has received sponsored research support from Almirall, Amphista therapeutics, Boehringer Ingelheim, Eisai, Nurix therapeutics, and Ono Pharmaceuticals. A. C. is a scientific founder, shareholder, and consultant of Amphista therapeutics. A. R. L. has consulted for Astex Therapeutics and has received research funding from Novo Nordisk. S. Ku. is a co-founder and shareholder of Proxygen GmbH and Solgate GmbH. G. E. W. is a founder and shareholder of Proxygen and Solgate Therapeutics. He is on the Research Review Committee of Almirall and coordinates a research collaboration between CeMM and Pfizer. S. F. reports equity ownership and membership on the Meryx Board of Directors and consulting or SAB relationships with Artios, Astex, Cullgen, Design Therapeutics, Flare, Mitokinin, Pathios, ReViral and eFFector. This communication reflects the views of the authors and neither IMI nor the European Union, EFPIA or any Associated Partners are liable for any use that may be made of the information contained herein., (This journal is © The Royal Society of Chemistry.)

Published
2021
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73. Discovery of 3-Cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonist.

Author

Schnute ME, Wennerstål M, Alley J, Bengtsson M, Blinn JR, Bolten CW, Braden T, Bonn T, Carlsson B, Caspers N, Chen M, Choi C, Collis LP, Crouse K, Färnegårdh M, Fennell KF, Fish S, Flick AC, Goos-Nilsson A, Gullberg H, Harris PK, Heasley SE, Hegen M, Hromockyj AE, Hu X, Husman B, Janosik T, Jones P, Kaila N, Kallin E, Kauppi B, Kiefer JR, Knafels J, Koehler K, Kruger L, Kurumbail RG, Kyne RE Jr, Li W, Löfstedt J, Long SA, Menard CA, Mente S, Messing D, Meyers MJ, Napierata L, Nöteberg D, Nuhant P, Pelc MJ, Prinsen MJ, Rhönnstad P, Backström-Rydin E, Sandberg J, Sandström M, Shah F, Sjöberg M, Sundell A, Taylor AP, Thorarensen A, Trujillo JI, Trzupek JD, Unwalla R, Vajdos FF, Weinberg RA, Wood DC, Xing L, Zamaratski E, Zapf CW, Zhao Y, Wilhelmsson A, and Berstein G

Subjects
Administration, Oral, Animals, Biological Availability, Drug Evaluation, Preclinical, Humans, Mice, Pyridines pharmacokinetics, Th17 Cells drug effects, Th17 Cells metabolism, Drug Design, Drug Inverse Agonism, Nuclear Receptor Subfamily 1, Group F, Member 3 agonists, Pyridines administration & dosage, Pyridines pharmacology
Abstract

The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist, demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.

Published
2018
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