PRN694

PRN694 is an irreversible, highly selective and potent covalent interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) dual inhibitor with IC₅₀s of 0.3 nM and 1.4 nM, respectively. PRN694 exhibits extended target residence time on ITK and RLK, enabling durable attenuation of effector cells in vitro and in vivo^[1]. IC50 & Target: IC50: 0.3 nM (ITK), 1.4 nM (RLK), 3.3 nM (TEC), 17 nM (BTK), 17 nM (BMX), 30 nM (JAK3), 125 nM (BLK)^[1] In Vitro: PRN694 inhibits TEC, BTK, BMX, BLK, JAK3 with IC₅₀s of 3.3, 17, 17, 125, 30 nM, respectively^[1].
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. PRN694 significantly attenuates NK cell FcR-induced killing at concentrations exceeding 0.37 μM^[1].
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]. In Vivo: 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].