3KRL

cFMS Tyrosine kinase in complex with 5-Cyano-furan-2-carboxylic acid [4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenyl]-amide

3KRL の概要

• エントリーDOI: 10.2210/pdb3krl/pdb
• 関連するPDBエントリー: 3KRJ
• 分子名称: Macrophage colony-stimulating factor 1 receptor, Basic fibroblast growth factor receptor 1, 5-cyano-N-[4-(4-methylpiperazin-1-yl)-2-piperidin-1-ylphenyl]furan-2-carboxamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: kinase, inhibitor, chimera, atp-binding, disulfide bond, glycoprotein, immunoglobulin domain, membrane, nucleotide-binding, phosphoprotein, proto-oncogene, receptor, transferase, transmembrane, tyrosine-protein kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens; 詳細
• 細胞内の位置: Cell membrane; Single-pass type I membrane protein: P07333
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38554.02

構造登録者

Schubert, C. (登録日: 2009-11-18, 公開日: 2010-12-01, 最終更新日: 2023-09-06)

主引用文献

Illig, C.R.,Manthey, C.L.,Wall, M.J.,Meegalla, S.K.,Chen, J.,Wilson, K.J.,Ballentine, S.K.,Desjarlais, R.L.,Schubert, C.,Crysler, C.S.,Chen, Y.,Molloy, C.J.,Chaikin, M.A.,Donatelli, R.R.,Yurkow, E.,Zhou, Z.,Player, M.R.,Tomczuk, B.E.
Optimization of a Potent Class of Arylamide Colony-Stimulating Factor-1 Receptor Inhibitors Leading to Anti-inflammatory Clinical Candidate 4-Cyano-N-[2-(1-cyclohexen-1-yl)-4-[1-[(dimethylamino)acetyl]-4-piperidinyl]phenyl]-1H-imidazole-2-carboxamide (JNJ-28312141).
J.Med.Chem., 54:7860-7883, 2011

PubMed Abstract: A class of potent inhibitors of colony-stimulating factor-1 receptor (CSF-1R or FMS), as exemplified by 8 and 21, was optimized to improve pharmacokinetic and pharmacodynamic properties and potential toxicological liabilities. Early stage absorption, distribution, metabolism, and excretion assays were employed to ensure the incorporation of druglike properties resulting in the selection of several compounds with good activity in a pharmacodynamic screening assay in mice. Further investigation, utilizing the type II collagen-induced arthritis model in mice, culminated in the selection of anti-inflammatory development candidate JNJ-28312141 (23, FMS IC(50) = 0.69 nM, cell assay IC(50) = 2.6 nM). Compound 23 also demonstrated efficacy in rat adjuvant and streptococcal cell wall-induced models of arthritis and has entered phase I clinical trials.

PubMed: 22039836
DOI: 10.1021/jm200900q

実験手法

X-RAY DIFFRACTION (2.4 Å)