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

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• 作者：Jean-Baptiste Telliez ; Martin E. Dowty ; Lu Wang ; Jason Jussif ; Tsung Lin ; Li Li ; Erick Moy ; Paul Balbo ; Wei Li ; Yajuan Zhao ; Kimberly Crouse ; Caitlyn Dickinson ; Peter Symanowicz ; Martin Hegen ; Mary Ellen Banker ; Fabien Vincent ; Ray Unwalla ; Sidney Liang ; Adam M. Gilbert ; Matthew F. Brown ; Matthew Hayward ; Justin Montgomery ; Xin Yang ; Jonathan Bauman ; John I. Trujillo ; Agustin Casimiro-Garcia ; Felix F. Vajdos ; Louis Leung ; Kieran F. Geoghegan ; Amira Quazi ; Dejun Xuan ; Lyn Jones ; Erik Hett ; Katherine Wright ; James D. Clark ; Atli Thorarensen
• 刊名：ACS Chemical Biology
• 出版年：2016
• 出版时间：December 16, 2016
• 年：2016
• 卷：11
• 期：12
• 页码：3442-3451
• 全文大小：635K
• ISSN：1554-8937

文摘

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.