6gl3
Crystal structure of human Phosphatidylinositol 4-kinase III beta (PI4KIIIbeta) in complex with ligand 44
Structural highlights
Function[PI4KB_HUMAN] Phosphorylates phosphatidylinositol (PI) in the first committed step in the production of the second messenger inositol-1,4,5,-trisphosphate (PIP). May regulate Golgi disintegration/reorganization during mitosis, possibly via its phosphorylation. Involved in Golgi-to-plasma membrane trafficking (By similarity).[1] [2] [3] Publication Abstract from PubMedThe primary target of a novel series of immunosuppressive 7-piperazin-1-ylthiazolo[5,4- d]pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIbeta. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physicochemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound 22 was initially identified and profiled in vivo, before further modifications led to the discovery of 44 (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmacokinetic profile. A co-crystal structure of 44 with PI4KIIIbeta was solved, confirming the binding mode of this class of inhibitor. The much-improved in vivo profile of 44 positions it as an ideal tool compound to further establish the link between PI4KIIIbeta inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses in vivo. Discovery of a Potent, Orally Bioavailable PI4KIIIbeta Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment in Vivo.,Reuberson J, Horsley H, Franklin RJ, Ford D, Neuss J, Brookings D, Huang Q, Vanderhoydonck B, Gao LJ, Jang MY, Herdewijn P, Ghawalkar A, Fallah-Arani F, Khan AR, Henshall J, Jairaj M, Malcolm S, Ward E, Shuttleworth L, Lin Y, Li S, Louat T, Waer M, Herman J, Payne A, Ceska T, Doyle C, Pitt W, Calmiano M, Augustin M, Steinbacher S, Lammens A, Allen R J Med Chem. 2018 Aug 9;61(15):6705-6723. doi: 10.1021/acs.jmedchem.8b00521. Epub , 2018 Jul 19. PMID:29952567[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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