The phosphatidylinositol 4-kinases (PI4Ks) play prominent roles in compartment identity. PI4KIIIβ is one of four mammalian PI4K enzymes that phosphorylate phosphatidylinositol to generate phosphatidylinositol 4-phosphate (PI4P). PI4KIIIβ localizes primarily at the Golgi and is essential for Golgi formation and function. PI4KIIIβ activity is essential for replication of a range of RNA viruses, including enteroviruses, SARS coronavirus, and hepatitis C virus[1]. UCB9608 is a potent, selective and orally active PI4KIIIβ inhibitor, with an IC50 value of 11 nM. UCB9608 is selective for PI4KIIIβ over PI3KC2 α, β, and γ lipid kinases. UCB9608 inhibits human mixed lymphocyte reaction, with an IC50 value of 37 nM. UCB9608 improves metabolic stability and exhibits excellent pharmacokinetic profile, acts as a potent immunosuppressive agent[2]. UCB9608 had very low CLb, commensurate with its low CLint in MLM, leading to a half-life of 1.4 h, with high bioavailability, and low inter-individual variability. UCB9608 could achieve high and consistently reproducible exposures in Balb/C mice. It could also prevent the rejection of a heterotopic murine cardiac allograft at a dose of 5 mpk. The excellent ADME properties of UCB9608 make it an ideal molecule to develop the understanding of the role of this novel class of PI4KIIIβ inhibitors on immune cell activation[2].
作用机制
The amino pyrimidine of UCB9608 makes a bidentate interaction with the Val613 backbone. The urea NH and carbonyl of UCB9608 form H-bonds with the main-chain Gly675 carbonyl and the side-chain NH2 of Asn390 respectively.
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