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
  • 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.
PMID: 27791347 DOI: 10.1021/acschembio.6b00677
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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