KDU691 is an orally active imidazopyrazine class antiparasitic that inhibits Plasmodium & Cryptosporidium phosphatidylinositol-4-OH kinase, PI(4)K, in an ATP-competitive, highly potent and selective manner (IC50/[ATP] = 1.5 nM/10 μM/P. vivax & 17 nM/3 μM/C. parvum PI(4)K) with little or no activity against human PI3Kα/β/γ/δ, PI4KIIIβ, VPS34, and 36 human protein kinases. KDU691 is effective against human pathogens P. falciparum, P. vivax, C. parvum and C. hominis, as well as simian parasite P. cynomolgi. KDU691 blocks Plasmodium development in all life-cycle stages and displays in vivo efficacy in murine models of malaria and cryptosporidiosis.
Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular
Malaria control and elimination are threatened by the emergence and spread of resistance to artemisinin-based combination therapies (ACTs). Experimental evidence suggests that when an artemisinin (ART)-sensitive (K13 wild-type) Plasmodium falciparum strain is exposed to ART derivatives such as dihydroartemisinin (DHA)
Antimicrobial agents and chemotherapy, 62(5) (2018-03-14)
Artemisinin (ART) resistance has spread through Southeast Asia, posing a serious threat to the control and elimination of malaria. ART resistance has been associated with mutations in the Plasmodium falciparum kelch-13 (Pfk13) propeller domain. Phenotypically, ART resistance is defined as
Antimicrobial agents and chemotherapy, 60(5), 2858-2863 (2016-03-02)
Two Plasmodium PI4 kinase (PI4K) inhibitors, KDU691 and LMV599, were selected for in vivo testing as causal prophylactic and radical-cure agents for Plasmodium cynomolgi sporozoite-infected rhesus macaques, based on their in vitro activity against liver stages. Animals were infected with
Eradication of malaria requires a novel type of drug that blocks transmission from the human to the mosquito host, but selection of such a drug is hampered by a lack of translational models. Experimental mosquito infections yield infection intensities that
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