Discovery of GS-9973, a Selective and Orally Efficacious Inhibitor of Spleen Tyrosine Kinase

被引:140
作者
Currie, Kevin S. [1 ]
Kropf, Jeffrey E. [1 ]
Lee, Tony [1 ]
Blomgren, Peter [1 ]
Xu, Jianjun [1 ]
Zhao, Zhongdong [1 ]
Gallion, Steve [5 ]
Whitney, J. Andrew [2 ]
Maclin, Deborah [3 ]
Lansdon, Eric B. [4 ]
Maciejewski, Patricia [2 ]
Rossi, Ann Marie [2 ]
Rong, Hong [2 ]
Macaluso, Jennifer [2 ]
Barbosa, James [2 ]
Di Paolo, Julie A. [2 ]
Mitchell, Scott A. [1 ]
机构
[1] Gilead Sci Inc, Dept Chem, Branford, CT 06405 USA
[2] Gilead Sci Inc, Dept Biol, Branford, CT 06405 USA
[3] Gilead Sci Inc, Dept Drug Metab, Branford, CT 06405 USA
[4] Gilead Sci Inc, Dept Struct Chem, Foster City, CA 94404 USA
[5] Atheon Pharma Inc, Dept Informat & Modeling, Waltham, MA 02451 USA
关键词
NON-HODGKIN-LYMPHOMA; RHEUMATOID-ARTHRITIS; FOSTAMATINIB DISODIUM; SYK; INFLAMMATION; DISEASE; MODELS; POTENT; ACTIVATION; EXPRESSION;
D O I
10.1021/jm500228a
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Spleen tyrosine kinase (Syk) is an attractive drug target in autoimmune, inflammatory, and oncology disease indications. The most advanced Syk inhibitor, R406, 1 (or its prodrug form fostamatinib, 2), has shown efficacy in multiple therapeutic indications, but its clinical progress has been hampered by dose-limiting adverse effects that have been attributed, at least in part, to the off-target activities of 1. It is expected that a more selective Syk inhibitor would provide a greater therapeutic window. Herein we report the discovery and optimization of a novel series of imidazo[1,2-a]pyrazine Syk inhibitors. This work culminated in the identification of GS-9973, 68, a highly selective and orally efficacious Syk inhibitor which is currently undergoing clinical evaluation for autoimmune and oncology indications.
引用
收藏
页码:3856 / 3873
页数:18
相关论文
共 52 条
[1]  
Alinari L, 2012, ONCOTARGET, V3, P203
[2]   BLNK mediates Syk-dependent Btk activation [J].
Baba, Y ;
Hashimoto, S ;
Matsushita, M ;
Watanabe, D ;
Kishimoto, T ;
Kurosaki, T ;
Tsukada, S .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (05) :2582-2586
[3]   An orally bioavailable spleen tyrosine kinase inhibitor delays disease progression and prolongs survival in murine lupus [J].
Bahjat, Frances Rena ;
Pine, Polly R. ;
Reitsma, Andrea ;
Cassafer, Gail ;
Baluom, Muhammad ;
Grillo, Sunny ;
Chang, Betty ;
Zhao, Fei Fei ;
Payan, Donald G. ;
Grossbard, Elliott B. ;
Daikh, David I. .
ARTHRITIS AND RHEUMATISM, 2008, 58 (05) :1433-1444
[4]   Carboxylic Acid (Bio)Isosteres in Drug Design [J].
Ballatore, Carlo ;
Huryn, Donna M. ;
Smith, Amos B., III .
CHEMMEDCHEM, 2013, 8 (03) :385-395
[5]   R406, an orally available spleen tyrosine kinase inhibitor blocks Fc receptor signaling and reduces immune complex-mediated inflammation [J].
Braselmann, Sylvia ;
Taylor, Vanessa ;
Zhao, Haoran ;
Wang, Su ;
Sylvain, Catherine ;
Baluom, Muhammad ;
Qu, Kunbin ;
Herlaar, Ellen ;
Lau, Angela ;
Young, Chi ;
Wong, Brian R. ;
Lovell, Scott ;
Sun, Thomas ;
Park, Gary ;
Argade, Ankush ;
Jurcevic, Stipo ;
Pine, Polly ;
Singh, Rajinder ;
Grossbard, Elliott B. ;
Payan, Donald G. ;
Masuda, Esteban S. .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2006, 319 (03) :998-1008
[6]   A novel spleen tyrosine kinase inhibitor blocks c-jun N-terminal kinase-mediated gene expression in synoviocytes [J].
Cha, HS ;
Boyle, DL ;
Inoue, T ;
Schoot, R ;
Tak, PP ;
Pine, P ;
Firestein, GS .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2006, 317 (02) :571-578
[7]   Specific Inhibition of Spleen Tyrosine Kinase Suppresses Leukocyte Immune Function and Inflammation in Animal Models of Rheumatoid Arthritis [J].
Coffey, Greg ;
DeGuzman, Francis ;
Inagaki, Mayuko ;
Pak, Yvonne ;
Delaney, Suzanne M. ;
Ives, Dan ;
Betz, Andreas ;
Jia, Zhaozhong J. ;
Pandey, Anjali ;
Baker, Dale ;
Hollenbach, Stanley J. ;
Phillips, David R. ;
Sinha, Uma .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2012, 340 (02) :350-359
[8]   Therapeutic Targeting of Syk in Autoimmune Diabetes [J].
Colonna, Lucrezia ;
Catalano, Geoffrey ;
Chew, Claude ;
D'Agati, Vivette ;
Thomas, James W. ;
Wong, F. Susan ;
Schmitz, Jochen ;
Masuda, Esteban S. ;
Reizis, Boris ;
Tarakhovsky, Alexander ;
Clynes, Raphael .
JOURNAL OF IMMUNOLOGY, 2010, 185 (03) :1532-1543
[9]   Comprehensive analysis of kinase inhibitor selectivity [J].
Davis, Mindy I. ;
Hunt, Jeremy P. ;
Herrgard, Sanna ;
Ciceri, Pietro ;
Wodicka, Lisa M. ;
Pallares, Gabriel ;
Hocker, Michael ;
Treiber, Daniel K. ;
Zarrinkar, Patrick P. .
NATURE BIOTECHNOLOGY, 2011, 29 (11) :1046-U124
[10]   Suppression of Skin and Kidney Disease by Inhibition of Spleen Tyrosine Kinase in Lupus-Prone Mice [J].
Deng, Guo-Min ;
Liu, Lena ;
Bahjat, Frances Rena ;
Pine, Polly R. ;
Tsokos, George C. .
ARTHRITIS AND RHEUMATISM, 2010, 62 (07) :2086-2092