ATI-2138 is a potent, selective, covalent and irreversible dual inhibitor of ITK/JAK3 with IC50 of 0.18 nM, 0.83 nM, and 0.52 nM for ITK, TXK, and JAK3 respectrively.
ATI-2138 is 27-fold less potent for inhibiting BTK and >4200-fold less potent for inhibiting the other JAK family members, JAK1, JAK2, and tyrosine kinase 2 (Tyk2).
ATI-2138 dose-dependently decreased JAK1/JAK3-dependent IL-2–stimulated STAT5 phosphorylation in human PBMCs with IC50 of 23.1 nM, with no inhibitory effect on the JAK1/JAK2-dependent IFNγ-induced STAT1 phosphorylation or the JAK2/Tyk2-dependent IL-12–induced STAT4 phosphorylation (>20 uM).
ATI-2138 inhibited anti-CD3–induced TCR-dependent activation and subsequent ITK/TXK-dependent phosphorylation of PLCγ1 in a concentration-dependent manner (IC50=7.6 nM.
ATI-2138 potently inhibited anti-CD3–stimulated IL-2 cytokine production (an ITK-dependent effect downstream of TCR stimulation) from PBMCs (IC50=8.6 nM),  inhibited IL-15-induced IFNγ production (IC50=2.6 nM).
ATI-2138 demonstrated disease-modifying activity in rodent models of arthritis and an adoptive T cell model of colitis.
ATI-2138 has the potential for enhanced therapeutic efficacy in the treatment of autoimmune and chronic inflammatory disease.