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

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Telliez JB, Dowty ME, Wang L, Jussif J, Lin T, Li L, Moy E, Balbo P, Li W, Zhao Y, Crouse K, Dickinson C, Symanowicz P, Hegen M, Banker ME, Vincent F, Unwalla R, Liang S, Gilbert AM, Brown MF, Hayward M, Montgomery J, Yang X, Bauman J, Trujillo JI, Casimiro-Garcia A, Vajdos FF, Leung L, Geoghegan KF, Quazi A, Xuan D, Jones L, Hett E, Wright K, Clark JD, Thorarensen A

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. Epub 2016 Nov 10.

PubMed ID

27791347 [ View in PubMed

]

Abstract

PF-06651600, a newly discovered potent JAK3-selective inhibitor, is highly efficacious at inhibiting gammac 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 gammac 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 TNFalpha and IL-1beta 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.

DrugBank Data that Cites this Article

Drugs

Ritlecitinib

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Ritlecitinib	Cytoplasmic tyrosine-protein kinase BMX	Protein	Humans	Yes	Inhibitor	Details
Ritlecitinib	Tyrosine-protein kinase BTK	Protein	Humans	Yes	Inhibitor	Details
Ritlecitinib	Tyrosine-protein kinase ITK/TSK	Protein	Humans	Yes	Inhibitor	Details
Ritlecitinib	Tyrosine-protein kinase JAK3	Protein	Humans	Yes	Inhibitor	Details
Ritlecitinib	Tyrosine-protein kinase TXK	Protein	Humans	Yes	Inhibitor	Details