UCT943, a Next-GenerationPlasmodium falciparumPI4K Inhibitor Preclinical Candidate for the Treatment of Malaria
ABSTRACTThe 2-aminopyridine MMV048 was the first drug candidate inhibitingPlasmodiumphosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistantPlasmodium falciparumandPlasmodium vivaxclinical isolates. Excellentin vitroantiplasmodial activity translated into high efficacy inPlasmodium bergheiand humanizedP. falciparumNOD-scid IL-2Rγnullmouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderatein vivointrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generationPlasmodiumPI4K inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria.