The phosphatidylinositol 4-kinases (PI4Ks) synthesize phosphatidylinositol 4-phosphate (PI4P), a key member of the phosphoinositide family. PI4P defines the membranes of Golgi and trans-Golgi network (TGN) and regulates trafficking to and from the Golgi.
In mammals there are four different PI4K enzymes, two type II enzymes (PI4KIIα and PI4KIIβ) and two type III enzymes (PI4KIIIα and PI4KIIIβ). PI4KIIIβ plays key roles in mediating lipid transport, cytokinesis, maintaining lysosomal identity, and in tandem with Rab GTPases plays key roles in regulating membrane trafficking. PI4KIIIβ is critical for mediating viral replication of a number of RNA viruses through the generation of PI4P enriched viral replication platforms. Small molecule inhibitors of PI4KIIIβ are potent anti-viral agents. Development of PI4KIIIβ as an effective drug target for anti-viral therapeutics requires the generation of highly potent and specific inhibitors.
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PI4KIIIβ-IN-9 is a potent and selective inhibitor of PI4KIIIβ (IC50=7 nM); displays >1000-fold selectivity over class I and class III PI3Ks; A KN-93 derivative with improved selectivity.
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.
BQR-695 (NVP-BQR695) is a highly potent, selective PI4KIIIβ inhibitor that has high potency against both the human (IC50 = 80 nM) and PvPI4K (IC50=3.5 nM) ; shows >100 fold more potent over all other class I and class III PI3K isoforms; induces a schizont-stage arrest in imidazopyrazine-treated parasites and exhibits cross-resistance with the imidazopyrazine-resistant lines; a novel antimalarial compound that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host.
KDU-691 is a potent, selective, orally active parasite PI4K inhibitor with IC50 of 1.5 nM for P. vivax PI4K (PvPI4K); shows IC50 of 58 nM, 36 nM and 196 nM against P. falciparum (Pf, boold stages), P. yoelii (Py, schizont) and P. cynomolgi (Pc, hypnozoites) respectively; shows fully protective effect against P. cynomolgi sporozoites in animal models.
UCB9608 (UCB-9608) is a potent, selective, orally bioavailable PI4KIIIβ inhibitor with IC50 of 11 nM; also shows an IC50 of 37 nM in the human mixed lymphocyte reaction (HuMLR) assay, only inhibits the PI4KIIIβ and PI3KC2 α, β and γ lipid kinases in apnel of 250 kinases tested at 10 uM; UCB9608 is vastly more soluble, selective compound with improved metabolic stability and excellent pharmacokinetic profile, significantly prolongs allogeneic organ engraftment in vivo.
PIK-93 is a potent, synthetic PI4K inhibitor with IC50 of 19 nM (PI4KIIIβ), also inhibits PI3Kγ and PI3Kα with IC50 of 16 nM and 39 nM, respectively; also inhibits other PI3Ks, including PI3Kα, β, and δ, with IC50 values of 39 nM, 0.59 uM, and 0.12 uM, shows no inhibitory effect against a panel of other kinases; significantly inhibits the conversion of [3H]serine-labeled endogenous ceramide to sphingomyelin, reduces carbachol-induced translocation of TRPC6 to the plasma membrane and net Ca2+ entry in T6.11 cells at 300 nM; also demonstrates anti-enterovirus effects by inhibition of both poliovirus and HCV replication with EC50 of 0.14 uM and 1.9 uM, respectively.
MMV390048(MMV 048;MMV 390048) is a novel potent Plasmodium PI4K inhibitor with IC50 of 28 nM against intraerythrocytic life cycle stages of P. falciparum (NF54 drug-sensitive strain); blocks all life cycle stages of the malaria parasite, exhibits full chemoprotection, delays relapse in a Plasmodium cynomolgi monkey model.
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