6GL3

Crystal structure of human Phosphatidylinositol 4-kinase III beta (PI4KIIIbeta) in complex with ligand 44

Summary for 6GL3

• Entry DOI: 10.2210/pdb6gl3/pdb
• Descriptor: Phosphatidylinositol 4-kinase beta,Phosphatidylinositol 4-kinase beta, (3~{S})-4-(6-azanyl-1-methyl-pyrazolo[3,4-d]pyrimidin-4-yl)-~{N}-(4-methoxy-2-methyl-phenyl)-3-methyl-piperazine-1-carboxamide (3 entities in total)
• Functional Keywords: pi4k kinase, immunosuppressive, phosphoinositol 4-kinase iiibeta, transplantation, human mixed lymphocyte reaction, selectivity profile, binding mode, solubility, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 88387.95

Authors

Lammens, A.,Augustin, M.,Steinbacher, S.,Reuberson, J. (deposition date: 2018-05-22, release date: 2018-08-15, Last modification date: 2024-05-15)

Primary citation

Reuberson, J.,Horsley, H.,Franklin, R.J.,Ford, D.,Neuss, J.,Brookings, D.,Huang, Q.,Vanderhoydonck, B.,Gao, L.J.,Jang, M.Y.,Herdewijn, P.,Ghawalkar, A.,Fallah-Arani, F.,Khan, A.R.,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.
Discovery of a Potent, Orally Bioavailable PI4KIII beta Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment in Vivo.
J. Med. Chem., 61:6705-6723, 2018

PubMed Abstract: The primary target of a novel series of immunosuppressive 7-piperazin-1-ylthiazolo[5,4- d]pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIβ. 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 PI4KIIIβ 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 PI4KIIIβ inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses in vivo.

PubMed: 29952567
DOI: 10.1021/acs.jmedchem.8b00521

Experimental method

X-RAY DIFFRACTION (2.77 Å)