Development of Selective Covalent Janus Kinase 3 Inhibitors

Tan, Li; Akahane, Koshi; McNally, Randall; Reyskens, Kathleen M. S. E.; Ficarro, Scott B.; Liu, Suhu; Herter-Sprie, Grit S.; Koyama, Shohei; Pattison, Michael J.; Labella, Katherine; Johannessen, Liv; Akbay, Esra A.; Wong, Kwok-Kin; Frank, David A.; Marto, Jarrod A.; Look, Thomas A.; Arthur, J. Simon C.; Eck, Michael J.; Gray, Nathanael S.

doi:10.1021/acs.jmedchem.5b00710

Cited by 122Cytokine Signaling Pathways and InteractionsSynthesis and biological activityProtein Tyrosine Phosphatases

Development of Selective Covalent Janus Kinase 3 Inhibitors

Open access

Tan, Li, Akahane, Koshi, McNally, Randall, Reyskens, Kathleen M. S. E., Ficarro, Scott B., Liu, Suhu, Herter-Sprie, Grit S., Koyama, Shohei +11 more·2015·Journal of Medicinal Chemistry

DOI 10.1021/acs.jmedchem.5b00710PMC PMC4777322

Open this paper in CoChat — free account

Abstract

The Janus kinases (JAKs) and their downstream effectors, signal transducer and activator of transcription proteins (STATs), form a critical immune cell signaling circuit, which is of fundamental importance in innate immunity, inflammation, and hematopoiesis, and dysregulation is frequently observed in immune disease and cancer. The high degree of structural conservation of the JAK ATP binding pockets has posed a considerable challenge to medicinal chemists seeking to develop highly selective inhibitors as pharmacological probes and as clinical drugs. Here we report the discovery and optimization of 2,4-substituted pyrimidines as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Investigation of structure-activity relationship (SAR) utilizing biochemical and transformed Ba/F3 cellular assays resulted in identification of potent and selective inhibitors such as compounds 9 and 45. A 2.9 Å cocrystal structure of JAK3 in complex with 9 confirms the covalent interaction. Compound 9 exhibited decent pharmacokinetic properties and is suitable for use in vivo. These inhibitors provide a set of useful tools to pharmacologically interrogate JAK3-dependent biology.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1021/acs.jmedchem.5b00710

Cites

78 of 78 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

The shared features of JAK3 and mutant EGFR(T790M) enabled discovery of potent JAK3-selective covalent inhibitors starting from an EGFR inhibitor.
“These shared features enabled the discovery of potent JAK3-selective covalent inhibitors using an EGFR inhibitor as a starting point”
From Advances in covalent drug discovery (2022) · cites this paper as [79]
Covalent targeting of JAK3 Cys909 yields inhibitors selective for JAK3 over other JAK family members for autoimmune diseases.
“Covalent targeting of the non-conserved Cys909 of JAK3 has yielded inhibitors selective for JAK3 over other JAK family members for the treatment of autoimmune diseases77–81.”
From Advances in covalent drug discovery (2022) · cites this paper as [79]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Features and development of Coot
Emsley, P., Lohkamp, B., Scott, W. G., & Cowtan, K. D. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910007493 · Cited by 27,510 · see citing works
PHENIX : a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkóczi, G., Chen, V. B., Davis, I. W., Echols, N., Headd, J. J., Hung, L.-W., Kapral, G. J., Grosse-Kunstleve, R. W., et al. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909052925 · Cited by 23,716 · see citing works
Phaser crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612 · see citing works
XDS
Kabsch, W. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909047337 · Cited by 16,463 · see citing works
Overview of the CCP 4 suite and current developments
Winn, M. D., Ballard, C. C., Cowtan, K. D., Dodson, E. J., Emsley, P., Evans, P. R., Keegan, R. M., Krissinel, E. B., Leslie, A. G. W., McCoy, A., et al. (2011) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910045749 · Cited by 12,353 · see citing works
Jak-STAT Pathways and Transcriptional Activation in Response to IFNs and Other Extracellular Signaling Proteins
Darnell, J. E., Kerr, L. M., & Stark, G. R. (1994) · Science · doi:10.1126/science.8197455 · Cited by 6,080 · see citing works
PRODRG: a tool for high-throughput crystallography of protein–ligand complexes
Schüttelkopf, A. W., & van Aalten, D. M. F. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904011679 · Cited by 4,815 · see citing works
Scaling and assessment of data quality
Evans, P. (2005) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444905036693 · Cited by 4,391 · see citing works
AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer
Cross, D. A. E., Ashton, S. E., Ghiorghiu, S., Eberlein, C., Nebhan, C. A., Spitzler, P. J., Orme, J. P., Finlay, M. R. V., Ward, R. A., Mellor, M. J., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0337 · Cited by 2,246 · see citing works
The JAK-STAT Pathway at Twenty
Stark, G. R., & Darnell, J. E., Jr. (2012) · Immunity · doi:10.1016/j.immuni.2012.03.013 · Cited by 1,523 · see citing works
The JAK-STAT Pathway: Impact on Human Disease and Therapeutic Intervention
O'Shea, J., Schwartz, D., Villarino, A. V., Gadina, M., Mcinnes, I., & Laurence, A. (2015) · Annual Review of Medicine · doi:10.1146/annurev-med-051113-024537 · Cited by 1,472 · see citing works
BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models
Li, D., Ambrogio, L., Shimamura, T., Kubo, S., Takahashi, M., Chirieac, L. R., Padera, R. F., Shapiro, G. I., Baum, A., Himmelsbach, F., et al. (2008) · Oncogene · doi:10.1038/onc.2008.109 · Cited by 1,447 · see citing works
Self-citation
Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors
Akbay, E. A., Koyama, S., Carretero, J., Altabef, A. B., Tchaicha, J. H., Christensen, C. L., Mikse, O. R., Cherniack, A. D., Beauchamp, E. M., Pugh, T. J., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0310 · Cited by 1,237 · see citing works
Self-citation
Janus kinases in immune cell signaling
Ghoreschi, K., Laurence, A., & O’Shea, J. J. (2009) · Immunological Reviews · doi:10.1111/j.1600-065x.2008.00754.x · Cited by 1,149 · see citing works
Cytokine Signaling in 2002
O’Shea, J. J., Gadina, M., & Schreiber, R. D. (2002) · Cell · doi:10.1016/s0092-8674(02)00701-8 · Cited by 1,119 · see citing works
LKB1 modulates lung cancer differentiation and metastasis
Ji, H., Ramsey, M. R., Hayes, D. N., Fan, C., McNamara, K., Kozlowski, P., Torrice, C., Wu, M. C., Shimamura, T., Perera, S. A., et al. (2007) · Nature · doi:10.1038/nature06030 · Cited by 1,064 · see citing works
Self-citation
New insights into the regulation of T cells by γc family cytokines
Rochman, Y., Spolski, R. J., & Leonard, W. J. (2009) · Nature reviews. Immunology · doi:10.1038/nri2580 · Cited by 1,056 · see citing works
Novel mutant-selective EGFR kinase inhibitors against EGFR T790M
Zhou, W., Ercan, D., Chen, L., Yun, C.-H., Li, D., Capelletti, M., Cortot, A. B., Chirieac, L., Iacob, R. E., Padera, R., et al. (2009) · Nature · doi:10.1038/nature08622 · Cited by 1,013 · see citing works
Self-citation
Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms
Quintás-Cardama, A., Vaddi, K., Liu, P., Manshouri, T., Li, J., Scherle, P. A., Caulder, E., Wen, X., Li, Y., Waeltz, P., et al. (2010) · Blood · doi:10.1182/blood-2009-04-214957 · Cited by 843 · see citing works
Prevention of Organ Allograft Rejection by a Specific Janus Kinase 3 Inhibitor
Changelian, P. S., Flanagan, M. E., Ball, D. J., Kent, C. R., Magnuson, K. S., Martin, W. H., Rizzuti, B. J., Sawyer, P. S., Perry, B. D., Brissette, W. H., et al. (2003) · Science · doi:10.1126/science.1087061 · Cited by 666 · see citing works
Developing Irreversible Inhibitors of the Protein Kinase Cysteinome
Liu, Q., Sabnis, Y. A., Zhao, Z., Zhang, T., Buhrlage, S. J., Jones, L. H., & Gray, N. S. (2013) · Chemistry & Biology · doi:10.1016/j.chembiol.2012.12.006 · Cited by 662 · see citing works
Self-citation
Discovery and Development of Janus Kinase (JAK) Inhibitors for Inflammatory Diseases
Clark, J. D., Flanagan, M. E., & Telliez, J. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm401490p · Cited by 615 · see citing works
Mechanisms of Jak/STAT Signaling in Immunity and Disease
Villarino, A. V., Kanno, Y., Ferdinand, J. R., & O’Shea, J. J. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1401867 · Cited by 554 · see citing works
A universal algorithm for fast and automated charge state deconvolution of electrospray mass-to-charge ratio spectra
Zhang, Z., & Marshall, A. G. (1998) · Journal of the American Society for Mass Spectrometry · doi:10.1016/s1044-0305(97)00284-5 · Cited by 511 · see citing works
Structural Biology of Shared Cytokine Receptors
Wang, X., Lupardus, P. J., LaPorte, S. L., & García, K. C. (2007) · Annual Review of Immunology · doi:10.1146/annurev.immunol.24.021605.090616 · Cited by 407 · see citing works
Discovery of Potent and Selective Covalent Inhibitors of JNK
Zhang, T., Iñesta-Vaquera, F., Niepel, M., Zhang, J., Ficarro, S. B., Machleidt, T., Xie, T., Marto, J. A., Kim, N., Sim, T., et al. (2012) · Chemistry & Biology · doi:10.1016/j.chembiol.2011.11.010 · Cited by 348 · see citing works
Self-citation
Activating alleles of JAK3 in acute megakaryoblastic leukemia.
Walters, D. K., Mercher, T., Gu, T., O'Hare, T., Tyner, J., Loriaux, M., Goss, V., Lee, K. A., Eide, C., Wong, M., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.06.002 · Cited by 347 · see citing works
Chemical and Computational Methods for the Characterization of Covalent Reactive Groups for the Prospective Design of Irreversible Inhibitors
Flanagan, M. E., Abramite, J. A., Anderson, D. P., AULABAUGH, A. E., Dahal, U. P., Gilbert, A. M., Li, C., Montgomery, J. I., Oppenheimer, S. R., Ryder, T. F., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm501412a · Cited by 337 · see citing works
Discovery of CP-690,550: a potent and selective Janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection.
Flanagan, M., Blumenkopf, T., Brissette, W., Brown, M. F., Casavant, J. M., Chang, S.-P., Doty, J. L., Elliott, E., Fisher, M., Hines, M., et al. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm1004286 · Cited by 334 · see citing works
Inborn Errors of Human JAKs and STATs
Casanova, J., Holland, S. M., & Notarangelo, L. D. (2012) · Immunity · doi:10.1016/j.immuni.2012.03.016 · Cited by 320 · see citing works
Cytokine receptor signaling through the Jak–Stat–Socs pathway in disease
O’Sullivan, L. A., Liongue, C., Lewis, R. S., Stephenson, S. E. M., & Ward, A. C. (2007) · Molecular Immunology · doi:10.1016/j.molimm.2006.11.025 · Cited by 308 · see citing works
Janus Kinase 3–Activating Mutations Identified in Natural Killer/T-cell Lymphoma
Koo, G. C., Tan, S., Tang, T. P. L., Poon, S. L., Allen, G. E., Tan, L. H. C., Chong, S. C., Ong, W. S., Tay, K. K. W., Tao, M., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0028 · Cited by 275 · see citing works
Self-citation
Covalent docking of large libraries for the discovery of chemical probes
London, N., Miller, R. M., Krishnan, S., Uchida, K., Irwin, J. J., Eidam, O., Gibold, L., Cimermančič, P., Bonnet, R., Shoichet, B. K., et al. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1666 · Cited by 274 · see citing works
Hematopoietic cytokine receptor signaling
Baker, S. J., Rane, S. G., & Reddy, E. P. (2007) · Oncogene · doi:10.1038/sj.onc.1210757 · Cited by 256 · see citing works
Ba/F3 cells and their use in kinase drug discovery
Warmuth, M., Kim, S., Gu, X.-J., Xia, G., & Adrián, F. (2007) · Current Opinion in Oncology · doi:10.1097/cco.0b013e328011a25f · Cited by 240 · see citing works
Small-molecule kinase inhibitors provide insight into Mps1 cell cycle function
Kwiatkowski, N. P., Jelluma, N., Filippakopoulos, P., Soundararajan, M., Manak, M. S., Kwon, M., Choi, H. G., Sim, T., Deveraux, Q. L., Rottmann, S., et al. (2010) · Nature Chemical Biology · doi:10.1038/nchembio.345 · Cited by 238 · see citing works
Self-citation
High-throughput kinase profiling as a platform for drug discovery
GOLDSTEIN, D. M., Gray, N. S., & Zarrinkar, P. P. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2541 · Cited by 218 · see citing works
Self-citation
CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients
Pardanani, A. D., Lasho, T. L., Smith, G. D., Burns, C. J., Fantino, E., & Tefferi, A. (2009) · Leukemia · doi:10.1038/leu.2009.50 · Cited by 210 · see citing works
Inhibition of JAKs in Macrophages Increases Lipopolysaccharide-Induced Cytokine Production by Blocking IL-10–Mediated Feedback
Pattison, M. J., MacKenzie, K. F., & Arthur, J. S. C. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1200310 · Cited by 180 · see citing works
Self-citation
Crystal structure of the Jak3 kinase domain in complex with a staurosporine analog
Boggon, T. J., Li, Y., Manley, P. W., & Eck, M. J. (2005) · Blood · doi:10.1182/blood-2005-02-0707 · Cited by 171 · see citing works
Self-citation
Characterization of Dasatinib and Its Structural Analogs as CYP3A4 Mechanism-Based Inactivators and the Proposed Bioactivation Pathways
Li, X., He, Y., Ruiz, C. H., Koenig, M., & Cameron, M. D. (2009) · Drug Metabolism and Disposition · doi:10.1124/dmd.108.025932 · Cited by 162 · see citing works
JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma
Bouchekioua, A., Scourzic, L., Wever, O. D., Zhang, Y., Cervera, P., Aline-Fardin, A., Mercher, T., Gaulard, P., Nyga, R., Jeziorowska, D., et al. (2013) · Leukemia · doi:10.1038/leu.2013.157 · Cited by 161 · see citing works
Selective JAK inhibitors in development for rheumatoid arthritis
Norman, P. (2014) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2014.918604 · Cited by 157 · see citing works
Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression
Liao, W., Spolski, R. J., Li, P., Du, N., West, E. E., Ren, M., Mitra, S., & Leonard, W. J. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1301138111 · Cited by 155 · see citing works
TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia
Sanda, T., Tyner, J. W., Gutiérrez, A., Ngo, V. N., Glover, J., Chang, B. H., Yost, A., Ma, W., Fleischman, A. G., Zhou, W., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0504 · Cited by 143 · see citing works
Self-citation
Transforming properties of chimeric TEL-JAK proteins in Ba/F3 cells
Penard‐Lacronique, V., Boureux, A., Monni, R., Dumon, S., Mauchauffé, M., Mayeux, P., Gouilleux, F., Berger, R., Gisselbrecht, S., Ghysdael, J., et al. (2000) · Blood · doi:10.1182/blood.v95.6.2076 · Cited by 133 · see citing works
High-Throughput Kinase Profiling: A More Efficient Approach toward the Discovery of New Kinase Inhibitors
Miduturu, C. V., Deng, X., Kwiatkowski, N. P., Yang, W., Brault, L., Filippakopoulos, P., Chung, E., Yang, Q., Schwaller, J., Knapp, S., et al. (2011) · Chemistry & Biology · doi:10.1016/j.chembiol.2011.05.010 · Cited by 124 · see citing works
Self-citation
A Randomized, Double‐Blind, Placebo‐Controlled, Twelve‐Week, Dose‐Ranging Study of Decernotinib, an Oral Selective JAK‐3 Inhibitor, as Monotherapy in Patients With Active Rheumatoid Arthritis
Fleischmann, R., DAMJANOV, N. S., Kivitz, A., Legedza, A. K., Hoock, T. C., & Kinnman, N. (2014) · Arthritis & Rheumatology · doi:10.1002/art.38949 · Cited by 112 · see citing works
Signaling by IL-2 and related cytokines: JAKs, STATs, and relationship to immunodeficiency
Johnston, J. A., Bacon, C. M., Riedy, M. C., et al. (1996) · Journal of Leukocyte Biology · doi:10.1002/jlb.60.4.441 · Cited by 112 · see citing works
Improved Electrospray Ionization Efficiency Compensates for Diminished Chromatographic Resolution and Enables Proteomics Analysis of Tyrosine Signaling in Embryonic Stem Cells
Ficarro, S. B., Zhang, Y., Lu, Y., Moghimi, A. R., Askenazi, M., Hyatt, E., Smith, E. D., Boyer, L. F., Schlaeger, T. M., Luckey, C. J., et al. (2009) · Analytical Chemistry · doi:10.1021/ac802720e · Cited by 110 · see citing works
Self-citation
Tricyclic Covalent Inhibitors Selectively Target Jak3 through an Active Site Thiol
Goedken, E. R., Argiriadi, M. A., Banach, D. L., Fiamengo, B. A., Foley, S. E., Frank, K. E., George, J. S., Harris, C. M., Hobson, A. D., Ihle, D. C., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.595181 · Cited by 101 · see citing works
Ibrutinib (PCI-32765), the First BTK (Bruton’s Tyrosine Kinase) Inhibitor in Clinical Trials
Brown, J. R. (2013) · Current Hematologic Malignancy Reports · doi:10.1007/s11899-012-0147-9 · Cited by 100 · see citing works
Identification of a Potent Janus Kinase 3 Inhibitor with High Selectivity within the Janus Kinase Family
Thoma, G., Nuninger, F., Falchetto, R. A., Hermes, E., Tavares, G., Vangrevelinghe, E., & Zerwes, H. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm101157q · Cited by 100 · see citing works
Therapy for myeloproliferative neoplasms: when, which agent, and how?
Geyer, H. L., & Mesa, R. A. (2014) · Blood · doi:10.1182/blood-2014-05-577635 · Cited by 97 · see citing works
JAK3: A two-faced player in hematological disorders
Cornejo, M., Boggon, T. J., & Mercher, T. (2009) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2009.09.004 · Cited by 86 · see citing works
Kaempferol Inhibits IL-4-Induced STAT6 Activation by Specifically Targeting JAK3
Cortés, J. R., Perez-G, M., Rivas, M. D., & Zamorano, J. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.6.3881 · Cited by 81 · see citing works
Development and Applications of a Broad-Coverage, TR-FRET-Based Kinase Binding Assay Platform
Lebakken, C. S., Riddle, S. M., Singh, U. P., Frazee, W. J., Eliason, H. C., Gao, Y. Q., Reichling, L. J., Marks, B. D., & Vogel, K. W. (2009) · SLAS DISCOVERY · doi:10.1177/1087057109339207 · Cited by 81 · see citing works
Advances in the Discovery of Selective JAK Inhibitors
Menet, C. J., Rompaey, L. V., & Geney, R. (2013) · Progress in medicinal chemistry · doi:10.1016/b978-0-444-62652-3.00004-1 · Cited by 80 · see citing works
Cross Talk between the Akt and p38α Pathways in Macrophages Downstream of Toll-Like Receptor Signaling
McGuire, V. A., Gray, A., Monk, C. E., et al. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01691-12 · Cited by 77 · see citing works
JAK/STAT signaling pathways and cancer. Janus kinases/signal transducers and activators of transcription.
Boudný, V., & Kovařík, J. (2002) · PubMed · Cited by 71 · see citing works
Long-term Benefit of PD-L1 Blockade in Lung Cancer Associated with JAK3 Activation
Allen, E. M. V., Golay, H. G., Liu, Y., Koyama, S., Wong, K. K. W., Taylor-Weiner, A. N., Giannakis, M., Harden, M. V., Rojas‐Rudilla, V., Chevalier, A. A., et al. (2015) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-15-0024 · Cited by 69 · see citing works
Self-citation
A role for phospholipids in the binding and metabolism of drugs by hepatic microsomes. Use of the fluorescent hydrophobic probe 1-anilinonaphthalene-8-sulphonate
Eling, T. E., & DiAugustine, R. P. (1971) · Biochemical Journal · doi:10.1042/bj1230539 · Cited by 68 · see citing works
Newly described activating JAK3 mutations in T-cell acute lymphoblastic leukemia
Bains, T., Heinrich, M. C., Loriaux, M., et al. (2012) · Leukemia · doi:10.1038/leu.2012.74 · Cited by 65 · see citing works
mzAPI: a new strategy for efficiently sharing mass spectrometry data
Askenazi, M., Parikh, J. R., & Marto, J. A. (2009) · Nature Methods · doi:10.1038/nmeth0409-240 · Cited by 62 · see citing works
Self-citation
3-Amido pyrrolopyrazine JAK kinase inhibitors: development of a JAK3 vs JAK1 selective inhibitor and evaluation in cellular and in vivo models.
Soth, M., Hermann, J., Yee, C., Alam, M., Barnett, J., Berry, P., Browner, M., Frank, K., Frauchiger, S., Harris, S., et al. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm301646k · Cited by 62 · see citing works
Image-guided radiotherapy platform using single nodule conditional lung cancer mouse models
Herter-Sprie, G. S., Korideck, H., Christensen, C. L., Herter, J. M., Rhee, K., Berbeco, R. I., Bennett, D. G., Akbay, E. A., Kozono, D., Mak, R. H., et al. (2014) · Nature Communications · doi:10.1038/ncomms6870 · Cited by 53 · see citing works
Self-citation
Investigational Janus kinase inhibitors
Tam, C. S. L., & Verstovšek, S. (2013) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2013.774373 · Cited by 48 · see citing works
4-(3'-Bromo-4'hydroxylphenyl)-amino-6,7-dimethoxyquinazoline: a novel quinazoline derivative with potent cytotoxic activity against human glioblastoma cells.
Narla, R. K., Liu, X.-P., Myers, D. E., et al. (1998) · PubMed · Cited by 41 · see citing works
Development of pyrimidine-based inhibitors of Janus tyrosine kinase 3
Chen, J. J., Thakur, K. D., Clark, M. P., et al. (2006) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2006.08.022 · Cited by 38 · see citing works
Selective JAK Inhibitors
Dymock, B. W., Yang, E. G., Chu-Farseeva, Y.-Y., et al. (2014) · Future Medicinal Chemistry · doi:10.4155/fmc.14.92 · Cited by 35 · see citing works
Design and Synthesis of Tricyclic JAK3 Inhibitors with Picomolar Affinities as Novel Molecular Probes
Gehringer, M., Pfaffenrot, E., Bauer, S. M., et al. (2014) · ChemMedChem · doi:10.1002/cmdc.201300520 · Cited by 34 · see citing works
Janus kinase inhibitors for the treatment of myeloproliferative neoplasms
Rosenthal, A. C., & Mesa, R. A. (2014) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2014.913024 · Cited by 33 · see citing works
Discovery of a series of novel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, as potent JAK3 kinase inhibitors
Jaime‐Figueroa, S., de Vicente, J., Hermann, J. C., Jahangir, A. M., Jin, S., Kuglstatter, A., Lynch, S. M., Menke, J. G., Niu, L., Patel, V. P., et al. (2013) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2013.03.015 · Cited by 33 · see citing works
The future of JAK inhibition in myelofibrosis and beyond
Mascarenhas, J. O., Cross, N. C. P., & Mesa, R. A. (2014) · Blood Reviews · doi:10.1016/j.blre.2014.06.002 · Cited by 29 · see citing works
Selective affinity-based probe for oncogenic kinases suitable for live cell imaging
Zambaldo, C., Sadhu, K. K., Karthikeyan, G., Barluenga, S., Daguer, J., & Winssinger, N. (2013) · Chemical Science · doi:10.1039/c3sc21856b · Cited by 23 · see citing works
Scaffold hopping towards potent and selective JAK3 inhibitors: Discovery of novel C-5 substituted pyrrolopyrazines
de Vicente, J., Lemoine, R. C., Bartlett, M. J., et al. (2014) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2014.09.031 · Cited by 21 · see citing works
Anilino-monoindolylmaleimides as potent and selective JAK3 inhibitors
McDonnell, M. E., Bian, H., Wrobel, J. E., et al. (2014) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2014.01.001 · Cited by 20 · see citing works
Inhibition of JAK3 with a novel, selective and orally active small molecule induces therapeutic response in T-cell malignancies
Ross, J. A., Spadaro, M., Rosado, D. C., et al. (2013) · Leukemia · doi:10.1038/leu.2013.309 · Cited by 15 · see citing works

Flagged first, then by citations

Research works printed but not linked: 3

[42]Kabsch W Xds Acta crystallographica Section D, Biological crystallography 2010 66 Pt 2 125 132 20124692 PMC2815665
[44]McCoy AJ Grosse-Kunstleve RW Adams PD Winn MD Storoni LC Read RJ Phaser crystallographic software Journal of applied crystallography 2007 40 Pt 4 658 674 19461840 PMC2483472
[47]Bricogne G Blanc E Brandl M Flensburg C Keller P Paciorek W Roversi P Sharff A Smart OS Vonrhein C Womack TO 2011 BUSTER version 2.10.2 Cambridge, United Kingdom Global Phasing Ltd

Sorted by citations

Advances in covalent drug discovery
Boike, L., Henning, N. J., & Nomura, D. K. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00542-z · Cited by 823 · see citing works
Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition
Telliez, J.-B., Dowty, M. E., Wang, L., Jussif, J., Lin, T., Li, L., Moy, E., Balbo, P., Li, W., Zhao, Y., et al. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.6b00677 · Cited by 204 · see citing works
Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans
Thorarensen, A., Dowty, M. E., Banker, M. E., Juba, B., Jussif, J., Lin, T., Vincent, F., Czerwinski, R. M., Casimiro-Garcia, A., Unwalla, R., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01694 · Cited by 176 · see citing works
Designing Irreversible Inhibitors—Worth the Effort?
González‐Bello, C. (2016) · ChemMedChem · doi:10.1002/cmdc.201500469 · Cited by 74 · see citing works
Discovery of highly potent, selective, covalent inhibitors of JAK3
Kempson, J., Ovalle, D., Guo, J., Wrobleski, S. T., Lin, S., Spergel, S. H., Duan, J. J.-W., Jiang, B., Lu, Z., Das, J., et al. (2017) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2017.09.023 · Cited by 32 · see citing works

[Advances in Janus kinase/signal transducer and activator of transcription signaling pathway and its targeted drugs in dermatosis and immune diseases].
Lu, C. C., & Leng, X. M. (2022) · PubMed · doi:10.3760/cma.j.cn112138-20210930-00669
Rapamycin-induced inhibition of Janus kinase/signal transducer and activator of transcription pathway affects expression of high-mobility group box 1 in rats with acute liver injury
Zhang, Y., Zhao, Z.-F., Han, D.-W., et al. (2006) · World Chinese Journal of Digestology · doi:10.11569/wcjd.v14.i19.1916 · Cited by 2 · see citing works
IL-15; B cell lymphoma 2 (BCL-2; BCL2); BCL-XL; janus kinase-3 (JAK-3); signal transducer and activator of transcription 5 (STAT5)
(2010) · Science-Business eXchange · doi:10.1038/scibx.2010.610
Janus kinase-signal transducer and activator of transcription signaling pathways in non-small cell lung cancer: research progress
Zhang, W., & Wei, Y. (2017) · Zhonghua shiyan waike zazhi · doi:10.3760/cma.j.issn.1001-9030.2017.09.059
JAK-STAT signaling pathways are activated in the brain following reovirus infection
Goody, R. J., Beckham, J. D., Rubtsova, K., et al. (2007) · Journal of NeuroVirology · doi:10.1080/13550280701344983 · Cited by 42 · see citing works

Authors: Tan, L., Akahane, K., McNally, R., Reyskens, K. M. S. E., Ficarro, S. B., Liu, S., Herter-Sprie, G. S., Koyama, S., Pattison, M. J., Labella, K., Johannessen, L., Akbay, E. A., Wong, K.-K., Frank, D. A., Marto, J. A., Look, T. A., Arthur, J. S. C., Eck, M. J., & Gray, N. S.
Affiliations: Harvard University (US)
University of Dundee (GB)
Corresponding author: Gray, Nathanael S.
ORCID: Tan, Li
Akahane, Koshi
McNally, Randall
Ficarro, Scott B.
Herter-Sprie, Grit S.
Koyama, Shohei
Pattison, Michael J.
Labella, Katherine
Akbay, Esra A.
Wong, Kwok-Kin
Frank, David A.
Marto, Jarrod A.
Arthur, J. Simon C.
Eck, Michael J.
Gray, Nathanael S.
Venue: Journal of Medicinal Chemistry
Publisher: American Chemical Society (ACS)
Published: 2015-08-18
Volume: 58
Issue: 16
Pages: 6589-6606
ISSN: 0022-2623 (ISSN-L)
1520-4804
DOI: 10.1021/acs.jmedchem.5b00710
PMC: PMC4777322
OpenAlex: W2227715305
Cited by: 122
References: 78
Citations by year: 2026: 9 · 2025: 8 · 2024: 11 · 2023: 13 · 2022: 13 · 2021: 9 · 2020: 12 · 2019: 8 · 2018: 8 · 2017: 14 · 2016: 16 · 2015: 1
FWCI: 6.26
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Journal of Medicinal Chemistry (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
Discovery Research Portal (University of Dundee) (submittedVersion)
Funders: Deutsche Forschungsgemeinschaft (HE 6897/1-1)
Topics: Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords: JAK3, JAK3 inhibitors, covalent inhibitors, STAT signaling, structure-activity relationship, Ba/F3 cells, co-crystal structure, pharmacokinetics, immune cell signaling, inflammation, hematopoiesis
MeSH terms: Animals, Antineoplastic Agents, Biological Availability, Cell Survival, Humans, Male, Models, Molecular, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Janus Kinase 3

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Development of Selective Covalent Janus Kinase 3 Inhibitors

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Self-check

Cites

Cited by

Related

Record

About these checks