2P55

X-ray structure of the human mitogen-activated protein kinase kinase 1 (MEK1) in a complex with ligand and MgATP

2P55 の概要

• エントリーDOI: 10.2210/pdb2p55/pdb
• 関連するPDBエントリー: 1S9I 1S9J
• 分子名称: Dual specificity mitogen-activated protein kinase kinase 1, MAGNESIUM ION, 2-[(4-ETHYNYL-2-FLUOROPHENYL)AMINO]-3,4-DIFLUORO-N-(2-HYDROXYETHOXY)BENZAMIDE, ... (5 entities in total)
• 機能のキーワード: protein kinase structure; mitogen activated protein kinase kinase; signal transduction; ligand co-complex, ternary co-complex with kinase, ligand and mgatp; non-competitive protein kinase inhibitor, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37741.25

構造登録者

Ohren, J.F.,Pavlovsky, A.G. (登録日: 2007-03-14, 公開日: 2007-10-02, 最終更新日: 2023-08-30)

主引用文献

Spicer, J.A.,Rewcastle, G.W.,Kaufman, M.D.,Black, S.L.,Plummer, M.S.,Denny, W.A.,Quin, J.,Shahripour, A.B.,Barrett, S.D.,Whitehead, C.E.,Milbank, J.B.,Ohren, J.F.,Gowan, R.C.,Omer, C.,Camp, H.S.,Esmaeil, N.,Moore, K.,Sebolt-Leopold, J.S.,Pryzbranowski, S.,Merriman, R.L.,Ortwine, D.F.,Warmus, J.S.,Flamme, C.M.,Pavlovsky, A.G.,Tecle, H.
4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase.
J.Med.Chem., 50:5090-5102, 2007

PubMed Abstract: A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synthesized using a combination of medicinal chemistry, computational chemistry, and structural elucidation. The effect of variation in the carboxamide side chain, substitution on the pyridone nitrogen, and replacement of the 4'-iodide were all investigated. This study afforded several compounds which were either equipotent or more potent than the clinical candidate CI-1040 (1) in an isolated enzyme assay, as well as murine colon carcinoma (C26) cells, as measured by suppression of phosphorylated ERK substrate. Most notably, pyridone 27 was found to be more potent than 1 in vitro and produced a 100% response rate at a lower dose than 1, when tested for in vivo efficacy in animals bearing C26 tumors.

PubMed: 17880056
DOI: 10.1021/jm0704548

実験手法

X-RAY DIFFRACTION (2.8 Å)