UCT943

UCT943 is a next-generation Plasmodium falciparum PI4K inhibitor. UCT943 inhibits the P. vivax PI4K (PvPI4K) enzyme with an IC₅₀ of 23 nM^[1]. In Vitro: UCT943 maintains high in vitro selectivity (>200-fold) for the parasite PvPI4K versus the human PI4Kβ isozyme (IC₅₀ of PI4Kβ, 5.4 μM), inhibition of which is linked to immunosuppressive effects^[1].
In vitro cytotoxicity of UCT943 is tested against L6 cells, chinese hamster ovarian (CHO), Vero, and HepG2 cells, with 50% cytotoxic concentrations (CC₅₀s) of 12, 17, 113, and 13 μM, respectively^[1]. In Vivo: UCT943 shows excellent in vivo efficacy in the Plasmodium berghei (10 mg/kg and 3 mg/kg; oral administration; daily; 4 days) and P. falciparum NSG (NOD-scid IL-2Rγ^null) mouse models (0.01, 0.1, 0.3, 1.1 and 10 mg/kg; oral administration; once per day; 4 days). When dosed at 10 mg/kg per os (p.o.), UCT943 reduces parasitemia by >99.9% in the mouse P. berghei infection model and cures all mice, with >30 mean survival days (MSD). At 3 mg/kg p.o., no complete cure is achieved, and MSD is 10 days, albeit parasitemia is reduced by 99%. The resulting 90% effective dose (ED₉₀) is 1.0 mg/kg p.o. in the P. berghei infection model. The ED₉₀ is 0.25 mg/kg in the P. falciparum-infected NSG mouse model^[1].