6GL9

Crystal structure of JAK3 in complex with Compound 10 (FM475)

6GL9 の概要

• エントリーDOI: 10.2210/pdb6gl9/pdb
• 関連するPDBエントリー: 6GLA 6GLB
• 分子名称: Tyrosine-protein kinase JAK3, (~{E})-3-[3-(3-cyclohexyl-3,5,8,10-tetrazatricyclo[7.3.0.0^{2,6}]dodeca-1(9),2(6),4,7,11-pentaen-4-yl)phenyl]prop-2-enenitrile, 1-phenylurea, ... (6 entities in total)
• 機能のキーワード: kinase, jak3, covalent inhibitor, reversible covalent inhibitor, induced pocket, arginine pocket, structural genomics consortium, sgc, transferase
• 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: 68832.83

構造登録者

Chaikuad, A.,Forster, M.,von Delft, F.,Edwards, A.M.,Arrowsmith, C.H.,Bountra, C.,Laufer, S.A.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2018-05-23, 公開日: 2018-06-27, 最終更新日: 2024-01-17)

主引用文献

Forster, M.,Chaikuad, A.,Dimitrov, T.,Doring, E.,Holstein, J.,Berger, B.T.,Gehringer, M.,Ghoreschi, K.,Muller, S.,Knapp, S.,Laufer, S.A.
Development, Optimization, and Structure-Activity Relationships of Covalent-Reversible JAK3 Inhibitors Based on a Tricyclic Imidazo[5,4- d]pyrrolo[2,3- b]pyridine Scaffold.
J. Med. Chem., 61:5350-5366, 2018

PubMed Abstract: Janus kinases are major drivers of immune signaling and have been the focus of anti-inflammatory drug discovery for more than a decade. Because of the invariable colocalization of JAK1 and JAK3 at cytokine receptors, the question if selective JAK3 inhibition is sufficient to effectively block downstream signaling has been highly controversial. Recently, we discovered the covalent-reversible JAK3 inhibitor FM-381 (23) featuring high isoform and kinome selectivity. Crystallography revealed that this inhibitor induces an unprecedented binding pocket by interactions of a nitrile substituent with arginine residues in JAK3. Herein, we describe detailed structure-activity relationships necessary for induction of the arginine pocket and the impact of this structural change on potency, isoform selectivity, and efficacy in cellular models. Furthermore, we evaluated the stability of this novel inhibitor class in in vitro metabolic assays and were able to demonstrate an adequate stability of key compound 23 for in vivo use.

PubMed: 29852068
DOI: 10.1021/acs.jmedchem.8b00571

実験手法

X-RAY DIFFRACTION (1.7 Å)