UCT943

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UCT943 (UCT-943) 是一种有效的、选择性的下一代恶性疟原虫 PI4K 抑制剂，IC50 为 23 nM。

UCT943 (UCT-943) is a potent, selective, next generation Plasmodium falciparum PI4K inhibitor with IC50 of 23 nM; displays higher asexual blood stage, transmission-blocking, and liver stage activity than MMV048 and is more potent against resistant P. falciparum and P. vivax clinical isolates; demonstrates excellent in vitro antiplasmodial activity in P. berghei and humanized P. falciparum mouse models.

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. 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.

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-2Rγnull) 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. Animal Model:Mice with P. berghei and P. falciparum NOD-scid IL-2Rγnull (NSG) models Dosage:10 mg/kg and 3 mg/kg for P. berghei model; 0.01, 0.1, 0.3, 1.1 and 10 mg/kg for P. falciparum NOD-scid IL-2Rγnull (NSG) model Administration:Oral administration; daily; 4 days for P. berghei modelOral administration; once per day; 4 days for P. falciparum NOD-scid IL-2Rγnull (NSG) model Result:The ED90 is 1.0 mg/kg in the P. berghei infection model. The ED90 is 0.25 mg/kg in the P. falciparum-infected NSG mouse model.

UCT 943 | UCT-943

PI3K/Akt/mTOR signaling

PI4K

PI4K

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1450666-80-4

427.431

C22H20F3N5O

>98% (HPLC)

In Vitro:?DMSO : 250 mg/mL (584.90 mM)

C1CN(CCN1)C(=O)C2=CC=C(C=C2)C3=CN=C(C(=N3)C4=CC=C(C=C4)C(F)(F)F)N

(4-(5-amino-6-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)phenyl)(piperazin-1-yl)methanone

(-20℃)

With Ice Pack

≥ 2 years