作者
Jean‐Baptiste Telliez,Martin E. Dowty,Lu Wang,Jason Jussif,Tsung H. Lin,Li Li,Erick Moy,Paul Balbo,Wei Li,Yajuan Zhao,Kimberly Crouse,Caitlyn Dickinson,Peter T. Symanowicz,Martin Hegen,Mary Ellen Banker,Fabien Vincent,Ray Unwalla,Steve H. L. Liang,Adam M. Gilbert,Matthew F. Brown,Matthew M. Hayward,Justin I. Montgomery,Xin Yang,Jonathan N. Bauman,John I. Trujillo,Agustin Casimiro‐Garcia,F.F. Vajdos,Louis Leung,Kieran F. Geoghegan,Amira Quazi,Dejun Xuan,Lyn H. Jones,Erik C. Hett,Katherine Wright,James D. Clark,Atli Thorarensen
摘要
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.