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

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

  • ACS Chem Biol. 2016 Dec 16;11(12):3442-3451. doi: 10.1021/acschembio.6b00677.
Jean-Baptiste Telliez 1 Martin E Dowty 2 Lu Wang 1 Jason Jussif 1 Tsung Lin 1 Li Li 1 Erick Moy 1 Paul Balbo 1 Wei Li 1 Yajuan Zhao 1 Kimberly Crouse 1 Caitlyn Dickinson 1 Peter Symanowicz 1 Martin Hegen 1 Mary Ellen Banker 3 Fabien Vincent 3 Ray Unwalla 4 Sidney Liang 5 Adam M Gilbert 5 Matthew F Brown 5 Matthew Hayward 5 Justin Montgomery 5 Xin Yang 2 Jonathan Bauman 2 John I Trujillo 5 Agustin Casimiro-Garcia 4 Felix F Vajdos 5 Louis Leung 2 Kieran F Geoghegan 5 Amira Quazi 1 Dejun Xuan 1 Lyn Jones 4 Erik Hett 4 Katherine Wright 2 James D Clark 1 Atli Thorarensen 4
Affiliations

Affiliations

  • 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.

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