6GL3

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

6GL3 の概要

• エントリーDOI: 10.2210/pdb6gl3/pdb
• 分子名称: 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)
• 機能のキーワード: pi4k kinase, immunosuppressive, phosphoinositol 4-kinase iiibeta, transplantation, human mixed lymphocyte reaction, selectivity profile, binding mode, solubility, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 88387.95

構造登録者

Lammens, A.,Augustin, M.,Steinbacher, S.,Reuberson, J. (登録日: 2018-05-22, 公開日: 2018-08-15, 最終更新日: 2024-05-15)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.77 Å)