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PRN694 is a highly selective and potent covalent inhibitor of T cell kinase (ITK) and resting lymphocyte kinase (RLK) with IC50s of 0.3 and 1.4 nM, respectively.

PRN694 exhibits high potency against ITK and RLK with IC50 values of 0.3 and 1.4 nM, respectively. With PRN694 pretreatment, CD3-mediated CD69 induction is inhibited both in Jurkat T-cells and freshly isolated primary CD4 or CD8 T-cells. Maximal inhibition of CD69 induction is achieved with PRN694 concentrations ranging from 0.1 to 1.0 μM. Immunoblot analysis of TCR activation pathways reveales that PRN694 blocks activation or nuclear translocation of NFAT1, JunB, pIκBα, and pERK. Results reveal inhibition of Ca2+ signaling with PRN694 at all concentrations above 1 nM. The data show that PRN694 significantly attenuates NK cell FcR-induced killing at concentrations exceeding 0.37 μM. Day 6 flow cytometry analysis reveals that PRN694 significantly inhibits the anti-CD3/CD28-induced proliferation of both CD4 and CD8 T-cells (p<0.01)[1].

The PRN694 occupancy of ITK is 98, 95, and 54% at 1, 6, and 14 h, respectively. The concentrations of PRN694 in the plasma are 2.8, 0.66, and 0.027 μM at 1, 6, and 14 h, respectively. At 14 h, the plasma level of PRN694 is over 10 fold lower than the IC50 in whole blood. RN694 treatment also results in significantly lower weights relative to vehicle (p<0.05)[1]. Colitis studies show reduced numbers of CD4+ T cells present in the colonic epithelium of PRN694-treated mice compare with controls[2].

[1]. Zhong Y, et al. Targeting interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) using a novel covalent inhibitor PRN694. J Biol Chem. 2015 Mar 6;290(10):5960-78. [2]. Cho HS, et al. A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression. J Immunol. 2015 Nov 15;195(10):4822-31.

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