5UIS

Crystal structure of IRAK4 in complex with compound 12

5UIS の概要

• エントリーDOI: 10.2210/pdb5uis/pdb
• 関連するPDBエントリー: 5UIQ 5UIR 5UIT 5UIU
• 分子名称: Interleukin-1 receptor-associated kinase 4, 4-{[(3R)-piperidin-3-yl]oxy}-6-[(propan-2-yl)oxy]quinoline-7-carboxamide (3 entities in total)
• 機能のキーワード: transferase, irak4, kinase, fragment screening
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : Q9NWZ3
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 147333.73

構造登録者

Han, S.,Chang, J.S. (登録日: 2017-01-14, 公開日: 2017-05-24, 最終更新日: 2024-10-23)

主引用文献

Lee, K.L.,Ambler, C.M.,Anderson, D.R.,Boscoe, B.P.,Bree, A.G.,Brodfuehrer, J.I.,Chang, J.S.,Choi, C.,Chung, S.,Curran, K.J.,Day, J.E.,Dehnhardt, C.M.,Dower, K.,Drozda, S.E.,Frisbie, R.K.,Gavrin, L.K.,Goldberg, J.A.,Han, S.,Hegen, M.,Hepworth, D.,Hope, H.R.,Kamtekar, S.,Kilty, I.C.,Lee, A.,Lin, L.L.,Lovering, F.E.,Lowe, M.D.,Mathias, J.P.,Morgan, H.M.,Murphy, E.A.,Papaioannou, N.,Patny, A.,Pierce, B.S.,Rao, V.R.,Saiah, E.,Samardjiev, I.J.,Samas, B.M.,Shen, M.W.H.,Shin, J.H.,Soutter, H.H.,Strohbach, J.W.,Symanowicz, P.T.,Thomason, J.R.,Trzupek, J.D.,Vargas, R.,Vincent, F.,Yan, J.,Zapf, C.W.,Wright, S.W.
Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design.
J. Med. Chem., 60:5521-5542, 2017

PubMed Abstract: Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.

PubMed: 28498658
DOI: 10.1021/acs.jmedchem.7b00231

実験手法

X-RAY DIFFRACTION (2.5 Å)