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Title: Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases

Abstract

Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. We report improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.

Authors:
ORCiD logo [1];  [1];  [1];  [1];  [2];  [2];  [2];  [3];  [4];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [3];  [3];  [2] more »;  [2];  [2];  [5];  [2];  [2];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1]; ORCiD logo [2]; ORCiD logo [1] « less
+ Show Author Affiliations
  1. Pfizer Inc, Cambridge, MA (United States)
  2. Pfizer Inc, Groton, CT (United States)
  3. Pfizer Inc, Kalamazoo, MI (United States)
  4. Pfizer Inc, Chesterfield, MO (United States)
  5. Pfizer Inc, Andover, MA (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1526050
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 61; Journal Issue: 3; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; Peptides and proteins; Ligands; ,Assays; Sulfones; Selectivity

Citation Formats

Vazquez, Michael L., Kaila, Neelu, Strohbach, Joseph W., Trzupek, John D., Brown, Matthew F., Flanagan, Mark E., Mitton-Fry, Mark J., Johnson, Timothy A., TenBrink, Ruth E., Arnold, Eric P., Basak, Arindrajit, Heasley, Steven E., Kwon, Soojin, Langille, Jonathan, Parikh, Mihir D., Griffin, Sarah H., Casavant, Jeffrey M., Duclos, Brian A., Fenwick, Ashley E., Harris, Thomas M., Han, Seungil, Caspers, Nicole, Dowty, Martin E., Yang, Xin, Banker, Mary Ellen, Hegen, Martin, Symanowicz, Peter T., Li, Li, Wang, Lu, Lin, Tsung H., Jussif, Jason, Clark, James D., Telliez, Jean-Baptiste, Robinson, Ralph P., and Unwalla, Ray. Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases. United States: N. p., 2018. Web. doi:10.1021/acs.jmedchem.7b01598.
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Vazquez, Michael L., Kaila, Neelu, Strohbach, Joseph W., Trzupek, John D., Brown, Matthew F., Flanagan, Mark E., Mitton-Fry, Mark J., Johnson, Timothy A., TenBrink, Ruth E., Arnold, Eric P., Basak, Arindrajit, Heasley, Steven E., Kwon, Soojin, Langille, Jonathan, Parikh, Mihir D., Griffin, Sarah H., Casavant, Jeffrey M., Duclos, Brian A., Fenwick, Ashley E., Harris, Thomas M., Han, Seungil, Caspers, Nicole, Dowty, Martin E., Yang, Xin, Banker, Mary Ellen, Hegen, Martin, Symanowicz, Peter T., Li, Li, Wang, Lu, Lin, Tsung H., Jussif, Jason, Clark, James D., Telliez, Jean-Baptiste, Robinson, Ralph P., & Unwalla, Ray. Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases. United States. https://doi.org/10.1021/acs.jmedchem.7b01598
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Vazquez, Michael L., Kaila, Neelu, Strohbach, Joseph W., Trzupek, John D., Brown, Matthew F., Flanagan, Mark E., Mitton-Fry, Mark J., Johnson, Timothy A., TenBrink, Ruth E., Arnold, Eric P., Basak, Arindrajit, Heasley, Steven E., Kwon, Soojin, Langille, Jonathan, Parikh, Mihir D., Griffin, Sarah H., Casavant, Jeffrey M., Duclos, Brian A., Fenwick, Ashley E., Harris, Thomas M., Han, Seungil, Caspers, Nicole, Dowty, Martin E., Yang, Xin, Banker, Mary Ellen, Hegen, Martin, Symanowicz, Peter T., Li, Li, Wang, Lu, Lin, Tsung H., Jussif, Jason, Clark, James D., Telliez, Jean-Baptiste, Robinson, Ralph P., and Unwalla, Ray. Wed . "Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases". United States. https://doi.org/10.1021/acs.jmedchem.7b01598. https://www.osti.gov/servlets/purl/1526050.
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@article{osti_1526050,
title = {Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases},
author = {Vazquez, Michael L. and Kaila, Neelu and Strohbach, Joseph W. and Trzupek, John D. and Brown, Matthew F. and Flanagan, Mark E. and Mitton-Fry, Mark J. and Johnson, Timothy A. and TenBrink, Ruth E. and Arnold, Eric P. and Basak, Arindrajit and Heasley, Steven E. and Kwon, Soojin and Langille, Jonathan and Parikh, Mihir D. and Griffin, Sarah H. and Casavant, Jeffrey M. and Duclos, Brian A. and Fenwick, Ashley E. and Harris, Thomas M. and Han, Seungil and Caspers, Nicole and Dowty, Martin E. and Yang, Xin and Banker, Mary Ellen and Hegen, Martin and Symanowicz, Peter T. and Li, Li and Wang, Lu and Lin, Tsung H. and Jussif, Jason and Clark, James D. and Telliez, Jean-Baptiste and Robinson, Ralph P. and Unwalla, Ray},
abstractNote = {Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. We report improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.},
doi = {10.1021/acs.jmedchem.7b01598},
journal = {Journal of Medicinal Chemistry},
number = 3,
volume = 61,
place = {United States},
year = {Wed Jan 03 00:00:00 EST 2018},
month = {Wed Jan 03 00:00:00 EST 2018}
}
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    Works referencing / citing this record:

    Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs
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    • Gadina, Massimo; Johnson, Catrina; Schwartz, Daniella
    • Journal of Leukocyte Biology, Vol. 104, Issue 3
    • DOI: 10.1002/jlb.5ri0218-084r

    JAK Inhibitors for Atopic Dermatitis: An Update
    journal, December 2018

    Selective JAKinibs: Prospects in Inflammatory and Autoimmune Diseases
    journal, January 2019

    Janus kinases to jakinibs: from basic insights to clinical practice
    journal, February 2019

    Emerging Topical and Systemic JAK Inhibitors in Dermatology
    journal, December 2019

    Emerging Topical and Systemic JAK Inhibitors in Dermatology
    text, January 2019

    • Solimani, Farzan; Meier, Katharina; Ghoreschi, Kamran
    • Charité - Universitätsmedizin Berlin
    • DOI: 10.17169/refubium-26067

    Selective JAKinibs: Prospects in Inflammatory and Autoimmune Diseases
    journal, January 2019

    Emerging Topical and Systemic JAK Inhibitors in Dermatology
    text, January 2019

    • Solimani, Farzan; Meier, Katharina; Ghoreschi, Kamran
    • Charité - Universitätsmedizin Berlin
    • DOI: 10.17169/refubium-26067

    On the Mechanism of Action of Anti-Inflammatory Activity of Hypericin: An In Silico Study Pointing to the Relevance of Janus Kinases Inhibition
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