title: 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.
authors: Inflammation and Immunology, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Jean-Baptiste
authors: JB
authors: Telliez
authors: Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
authors: Martin E
authors: ME
authors: Dowty
authors: Inflammation and Immunology, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Lu
authors: L
authors: Wang
authors: Inflammation and Immunology, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Jason
authors: J
authors: Jussif
authors: Inflammation and Immunology, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Tsung
authors: T
authors: Lin
authors: Inflammation and Immunology, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Li
authors: L
authors: Li
authors: Inflammation and Immunology, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Erick
authors: E
authors: Moy
authors: Inflammation and Immunology, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Paul
authors: P
authors: Balbo
authors: Inflammation and Immunology, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Wei
authors: W
authors: Li
authors: Inflammation and Immunology, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Yajuan
authors: Y
authors: Zhao
authors: Inflammation and Immunology, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Kimberly
authors: K
authors: Crouse
authors: Inflammation and Immunology, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Caitlyn
authors: C
authors: Dickinson
authors: Inflammation and Immunology, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Peter
authors: P
authors: Symanowicz
authors: Inflammation and Immunology, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Martin
authors: M
authors: Hegen
authors: Primary Pharmacology Group, Pfizer Worldwide R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
authors: Mary Ellen
authors: ME
authors: Banker
authors: Primary Pharmacology Group, Pfizer Worldwide R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
authors: Fabien
authors: F
authors: Vincent
authors: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Ray
authors: R
authors: Unwalla
authors: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
authors: Sidney
authors: S
authors: Liang
authors: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
authors: Adam M
authors: AM
authors: Gilbert
authors: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
authors: Matthew F
authors: MF
authors: Brown
authors: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
authors: Matthew
authors: M
authors: Hayward
authors: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
authors: Justin
authors: J
authors: Montgomery
authors: Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
authors: Xin
authors: X
authors: Yang
authors: Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
authors: Jonathan
authors: J
authors: Bauman
authors: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
authors: John I
authors: JI
authors: Trujillo
authors: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Agustin
authors: A
authors: Casimiro-Garcia
authors: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
authors: Felix F
authors: FF
authors: Vajdos
authors: Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
authors: Louis
authors: L
authors: Leung
authors: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
authors: Kieran F
authors: KF
authors: Geoghegan
authors: Inflammation and Immunology, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Amira
authors: A
authors: Quazi
authors: Inflammation and Immunology, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Dejun
authors: D
authors: Xuan
authors: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Lyn
authors: L
authors: Jones
authors: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Erik
authors: E
authors: Hett
authors: Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
authors: Katherine
authors: K
authors: Wright
authors: Inflammation and Immunology, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: James D
authors: JD
authors: Clark
authors: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors: Atli
authors: A
authors: Thorarensen
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology; D004195:Disease Models, Animal; D055808:Drug Discovery; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D053583:Interleukin-1beta; C000614924:PF-06651600; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D053613:Janus Kinase 1; D053616:Janus Kinase 3