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ACS Chem Biol. 2016 Dec 16;11(12):3442-3451. Epub 2016 Nov 10.

Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition.

Author information

1
Inflammation and Immunology, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
2
Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
3
Primary Pharmacology Group, Pfizer Worldwide R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
4
Worldwide Medicinal Chemistry, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
5
Worldwide Medicinal Chemistry, Pfizer Worldwide R&D , Eastern Point Road, Groton, Connecticut 06340, United States.

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT02309827.

PMID:
27791347
DOI:
10.1021/acschembio.6b00677
[Indexed for MEDLINE]

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