Porcupine (Porcn) is a membrane bound O-acyltransferase (MBOAT) family protein, which catalyzes the palmitoylation of Wnt to enable its exit from the secretory pathway and subsequent activation of cellular responses. IWP L6 is a subnanomolar Porcn inhibitor with IC50 value of 0.5 nM. In vitro, treatment of the HEK293 cells with 2.5 μM IWP L6 effectively suppressed the phosphorylation of the cytoplasmic Wnt pathway effector disheveled 2 (Dvl2)[2]. Treatment of T.cruzi trypomastigotes infection of Bone marrow-derived macrophages (BMM) with 20 μM IWP L6 inhibited both p-CaMKII upregulation and NFATc1 activation. IWP L6 at concentration of 20μM resulted in a inhibitory effect on intracellular parasite growth by inhibiting the secretion of Wnt proteins in T.cruzi trypomastigotes infection of BMM[3]. In vivo stability analysis of IWP L6 showed that IWP L6 was stable in human plasma over 24h, it was rapidly metabolized in rat plasma, murine plasma and the murine liver S9 fractions with t1/2 of 190 min, 2 min and 26 min, respectively. IWP L6 effectively inhibited posterior axis formation of juvenile zebrafish, a Wnt/β-catenin dependent developmental process, at concentration range of 1 – 5 μM[2]. Intraperitoneal administration of IWP L6 at 7.5 mg/kg could maintain inhibited both Wnt/β-catenin as well as Wnt/Ca2+ signaling pathways until 18 days post-infection in B6 mice infected with 5,000 T. cruzi trypomastigotes. In addition, treatment with IWP-L6 significantly reduced parasite load in liver and heart of B6 mice infected with 5,000 T. cruzi trypomastigotes during the chronic phase of the disease[3].
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