Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition
Abstract
PF-06651600, a newly discovered potent JAK3-selective inhibitor, is highly efficacious at inhibiting γc cytokine signaling, which is dependent on both JAK1 and JAK3. PF-06651600 allowed the comparison of JAK3-selective inhibition to pan-JAK or JAK1-selective inhibition, in relevant immune cells to a level that could not be achieved previously without such potency and selectivity. In vitro, PF-06651600 inhibits Th1 and Th17 cell differentiation and function, and in vivo it reduces disease pathology in rat adjuvant-induced arthritis as well as in mouse experimental autoimmune encephalomyelitis models. Importantly, by sparing JAK1 function, PF-06651600 selectively targets γc cytokine pathways while preserving JAK1-dependent anti-inflammatory signaling such as the IL-10 suppressive functions following LPS treatment in macrophages and the suppression of TNFα and IL-1β production in IL-27-primed macrophages. Thus, JAK3-selective inhibition differentiates from pan-JAK or JAK1 inhibition in various immune cellular responses, which could potentially translate to advantageous clinical outcomes in inflammatory and autoimmune diseases.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
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 [81]
Cites
Macrophage activation and polarization
Martinez, F. O. (2008) · Frontiers in Bioscience · doi:10.2741/2692 · Cited by 3,160 · see citing works
The resurgence of covalent drugs
Singh, J., Petter, R. C., Baillie, T. A., & Whitty, A. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3410 · Cited by 1,873 · see citing works
IL‐6: Regulator of Treg/Th17 balance
Kimura, A., & Kishimoto, T. (2010) · European Journal of Immunology · doi:10.1002/eji.201040391 · Cited by 1,605 · see citing works
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
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
IL-35-mediated induction of a potent regulatory T cell population
Collison, L. W., Chaturvedi, V., Henderson, A. L., Giacomin, P., Guy, C. S., Bankoti, J., Finkelstein, D., Forbes, K., Workman, C. J., Brown, S. A., et al. (2010) · Nature Immunology · doi:10.1038/ni.1952 · Cited by 870 · 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
Self-citationDiscovery 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
Self-citationActive induction of experimental allergic encephalomyelitis
Stromnes, I. M., & Goverman, J. M. (2006) · Nature Protocols · doi:10.1038/nprot.2006.285 · Cited by 572 · see citing works
Fitzgerald, D. C., Zhang, G.-X., El-Behi, M., Fonseca-Kelly, Z., Li, H., Yu, S., Saris, C. J. M., Gran, B., Ciric, B., & Rostami, A. (2007) · Nature Immunology · doi:10.1038/ni1540 · Cited by 529 · see citing works
Zhang, X. (2004) · International Immunology · doi:10.1093/intimm/dxh029 · Cited by 365 · see citing works
Targeting Th17 cells in autoimmune diseases
Yang, J., Sundrud, M. S., Skepner, J. E., & Yamagata, T. (2014) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2014.07.006 · Cited by 348 · see citing works
Fitzgerald, D. C., Ćirić, B., Touil, T., Harle, H., Grammatikopolou, J., Sarma, J. D., Gran, B., Zhang, G., & Rostami, A. M. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.5.3268 · Cited by 307 · see citing works
McCarthy, D. P., Richards, M. H., & Miller, S. D. (2012) · Methods in molecular biology · doi:10.1007/978-1-60761-720-4_19 · Cited by 209 · see citing works
Jak1 Has a Dominant Role over Jak3 in Signal Transduction through γc-Containing Cytokine Receptors
Haan, C., Rolvering, C., Raulf, F., Kapp, M., Drückes, P., Thoma, G., Behrmann, I., & Zerwes, H. (2011) · Chemistry & Biology · doi:10.1016/j.chembiol.2011.01.012 · Cited by 203 · see citing works
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
Bauman, J. N., Kelly, J. M., Tripathy, S., Zhao, S. X., Lam, W. W., Kalgutkar, A. S. S., & Obach, R. S. (2009) · Chemical Research in Toxicology · doi:10.1021/tx800407w · Cited by 139 · see citing works
Self-citationDevelopment of Selective Covalent Janus Kinase 3 Inhibitors
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., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00710 · Cited by 122 · see citing works
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
JAK Kinases in Health and Disease: An Update
Laurence, A. D. J., Pesu, M., Silvennoinen, O., & O’Shea, J. J. (2012) · The Open Rheumatology Journal · doi:10.2174/1874312901206010232 · Cited by 96 · see citing works
Farmer, L., Ledeboer, M., Hoock, T., Arnost, M., Bethiel, R. S., Bennani, Y., Black, J., Brummel, C. L., Chakilam, A. R., Dorsch, W., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00301 · Cited by 80 · see citing works
Kalliolias, G. D., Gordon, R. A., & Ivashkiv, L. B. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1001290 · Cited by 77 · see citing works
Tec Family Kinases in Inflammation and Disease
Horwood, N. J., Urbaniak, A. M., & Danks, L. (2012) · International Reviews of Immunology · doi:10.3109/08830185.2012.670334 · Cited by 73 · see citing works
Mahajan, S., Hogan, J. K., Shlyakhter, D., Oh, L., Salituro, F. G., Farmer, L. J., & Hoock, T. C. (2015) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.114.221176 · Cited by 64 · see citing works
Thorarensen, A., Banker, M. E., Fensome, A., Telliez, J., Juba, B. M., Vincent, F., Czerwiński, R., & Casimiro‐Garcia, A. (2014) · ACS Chemical Biology · doi:10.1021/cb5002125 · Cited by 62 · see citing works
Self-citationLeung, L. Y., Yang, X., Strelevitz, T. J., Montgomery, J. I., Brown, M. F., Zientek, M. A., Banfield, C. R., Gilbert, A. M., Thorarensen, A., & Dowty, M. E. (2016) · Drug Metabolism and Disposition · doi:10.1124/dmd.116.072983 · Cited by 52 · see citing works
Self-citationGehringer, M., Pfaffenrot, E., Bauer, S. M., et al. (2014) · ChemMedChem · doi:10.1002/cmdc.201300520 · Cited by 34 · see citing works
Vitamin D metabolism in rats with adjuvant-induced arthritis
Langman, C. B., Ford, K. K., Pachman, L. M., et al. (1990) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.5650050903 · Cited by 31 · see citing works
CI-1033, a pan-erbB tyrosine kinase inhibitor
Slichenmyer, W. J., Elliott, W. L., & Fry, D. W. (2001) · Seminars in Oncology · doi:10.1053/sonc.2001.28558 · Cited by 17 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
JAK inhibition as a therapeutic strategy for immune and inflammatory diseases
Schwartz, D. M., Kanno, Y., Villarino, A., Ward, M., Gadina, M., & O'Shea, J. J. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.201 · Cited by 1,266 · see citing works
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
Biology and regulation of IL-2: from molecular mechanisms to human therapy
Spolski, R., Li, P., & Leonard, W. J. (2018) · Nature Reviews Immunology · doi:10.1038/s41577-018-0046-y · Cited by 637 · see citing works
An Activity-Guided Map of Electrophile-Cysteine Interactions in Primary Human T Cells
Vinogradova, E. V., Zhang, X., Remillard, D., Lazar, D. C., Suciu, R. M., Wang, Y., Bianco, G., Yamashita, Y., Crowley, V. M., Schafroth, M. A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.07.001 · Cited by 351 · see citing works
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
Self-citationDiscovery 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
- Authors
- Telliez, J.-B., Dowty, M. E., Wang, L., Jussif, J., Lin, T., Li, L., Moy, E., Balbo, P., Li, W., Zhao, Y., Crouse, K., Dickinson, C., Symanowicz, P., Hegen, M., Banker, M. E., Vincent, F., Unwalla, R., Liang, S., Gilbert, A. M., Brown, M. F., Hayward, M., Montgomery, J., Yang, X., Bauman, J., Trujillo, J. I., Casimiro-Garcia, A., Vajdos, F. F., Leung, L., Geoghegan, K. F., Quazi, A., Xuan, D., Jones, L., Hett, E., Wright, K., Clark, J. D., & Thorarensen, A.
- Affiliations
- Pfizer (United States) (US)
- Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Corresponding author
- Telliez, Jean-Baptiste
- Thorarensen, Atli
- ORCID
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-11-10
- Volume
- 11
- Issue
- 12
- Pages
- 3442-3451
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- OpenAlex
- W2540499968
- Cited by
- 204
- References
- 29
- Citations by year
- 2026: 21 · 2025: 27 · 2024: 27 · 2023: 22 · 2022: 22 · 2021: 18 · 2020: 19 · 2019: 21 · 2018: 10 · 2017: 16
- FWCI
- 8.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- ACS Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- Th1 differentiation, Th17 cell differentiation, adjuvant-induced arthritis, experimental autoimmune encephalomyelitis, IL-10, IL-27, autoimmune disease, inflammatory diseases
- MeSH terms
- Animals, Arthritis, Experimental, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Humans, Macrophages, Models, Molecular, Pyrimidines, Pyrroles, Tumor Necrosis Factor-alpha, Interleukin-10, Th1 Cells, Protein Kinase Inhibitors, Mice, Rats, Interleukin-1beta, Janus Kinase 1, Janus Kinase 3, Drug Discovery, Th17 Cells
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
