8S85 の概要
| エントリーDOI | 10.2210/pdb8s85/pdb |
| 分子名称 | Tyrosine-protein kinase JAK1, ~{N}-(2-ethylphenyl)-~{N},1-dimethyl-imidazo[4,5-c]pyridin-6-amine, SODIUM ION, ... (4 entities in total) |
| 機能のキーワード | kinase, jak1, inhibitor, signaling protein |
| 由来する生物種 | Homo sapiens (human) |
| タンパク質・核酸の鎖数 | 2 |
| 化学式量合計 | 70094.84 |
| 構造登録者 | |
| 主引用文献 | Mammoliti, O.,Menet, C.,Cottereaux, C.,Blanc, J.,De Blieck, A.,Coti, G.,Geney, R.,Oste, L.,Ostyn, K.,Palisse, A.,Quinton, E.,Schmitt, B.,Borgonovi, M.,Parent, I.,Jagerschmidt, C.,De Vos, S.,Vayssiere, B.,Lopez-Ramos, M.,Shoji, K.,Brys, R.,Amantini, D.,Galien, R.,Joannesse, C. Design of a potent and selective dual JAK1/TYK2 inhibitor. Bioorg.Med.Chem., 114:117932-117932, 2024 Cited by PubMed Abstract: Janus kinase (JAK) inhibitors have gathered interest as treatments for several inflammatory and autoimmune diseases. The four first marketed inhibitors target JAK1, with varying selectivity towards other JAK family members, but none inhibit tyrosine kinase-2 (TYK2) at clinically relevant doses. TYK2 is required for the signaling of the interleukin (IL)-12 and IL-23 cytokines, which are key to the polarization of T1 and T17 cells, respectively; two cell subtypes that play major roles in inflammatory diseases. Herein, we report our effort towards the optimization of a potent and selective dual JAK1/TYK2 inhibitor series starting from a HTS hit. Structural information revealed vectors required to improve both JAK1 and TYK2 potency as well as selectivity towards JAK2. The potent inhibition of both JAK1 (3.5 nM) and TYK2 (5.7 nM) in biochemical assays by our optimized lead compound, as well as its notable selectivity against JAK2, were confirmed in cellular and whole blood assays. Inhibition of TYK2 by the lead compound was demonstrated by dose-dependent efficacy in an IL-23-induced psoriasis-like inflammation mouse model. PubMed: 39447537DOI: 10.1016/j.bmc.2024.117932 主引用文献が同じPDBエントリー |
| 実験手法 | X-RAY DIFFRACTION (1.75 Å) |
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