Protease-activated receptors are a family of G-protein-coupled receptors implicated in inflammation, cell differentiation and proliferation. AZ3451 is an inhibitor of wild-type protease-activated receptor 2 (PAR2) with an IC50 value of 23 nM. AZ3451 also showed inhibitory effect on PAR2s with a single-point mutation on N222Q, H227A, H227Q, D228A, D228N, H135Y, I327L, G157M, Y210L, and F154A with IC50 values of 12, 12, 25, 23, 4.3, 20, 32, 780, 570 and 370 nM, respectively. In 1321N1 cells overexpressing wild-type human PAR2, stimulation of 1321N1 with SLIGRL led to the phosphorylation of extracellular signal-regulated kinase (ERK), whereas the induction of ERK phosphorylation was completely inhibited by AZ3451 at the concentration of 10 μM. The IP-One HTRF assay in 1321N1 cells stably expressing human PAR2 showed that the IC50 value of AZ3451 was 23nM vs. SLIGRL. The FLIPR assay showed that the IC50 values of AZ3451 were 5.4 nM and 6.6 nM against SLIGRL and trypsin, respectively[1].
作用机制
AZ3451 is an antagonist of PAR2 that binds to a remote allosteric site outside the helical bundle of the receptor, preventing structural rearrangements required for receptor activation[1].
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