3OS3

Mitogen-activated protein kinase kinase 1 (MEK1) in complex with CH4858061 and MgATP

3OS3 の概要

• エントリーDOI: 10.2210/pdb3os3/pdb
• 関連するPDBエントリー: 3ORN
• 分子名称: Dual specificity mitogen-activated protein kinase kinase 1, ADENOSINE-5'-TRIPHOSPHATE, 2-[(4-ethynyl-2-fluorophenyl)amino]-3,4-difluoro-N-(2-hydroxyethoxy)-5-{[(2-hydroxyethoxy)imino]methyl}benzamide, ... (5 entities in total)
• 機能のキーワード: kinase, kinase inhibitor, allosteric, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens; 詳細
• 細胞内の位置: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome : Q02750
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35208.29

構造登録者

Lukacs, C.M.,Janson, C.,Schuck, V.,Belunis, C. (登録日: 2010-09-08, 公開日: 2011-07-27, 最終更新日: 2024-02-21)

主引用文献

Isshiki, Y.,Kohchi, Y.,Iikura, H.,Matsubara, Y.,Asoh, K.,Murata, T.,Kohchi, M.,Mizuguchi, E.,Tsujii, S.,Hattori, K.,Miura, T.,Yoshimura, Y.,Aida, S.,Miwa, M.,Saitoh, R.,Murao, N.,Okabe, H.,Belunis, C.,Janson, C.,Lukacs, C.,Schuck, V.,Shimma, N.
Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent.
Bioorg.Med.Chem.Lett., 21:1795-1801, 2011

PubMed Abstract: The MAP kinase pathway is one of the most important pathways involved in cell proliferation and differentiation, and its components are promising targets for antitumor drugs. Design and synthesis of a novel MEK inhibitor, based on the 3D-structural information of the target enzyme, and then multidimensional optimization including metabolic stability, physicochemical properties and safety profiles were effectively performed and led to the identification of a clinical candidate for an orally available potent MEK inhibitor, CH4987655, possessing a unique 3-oxo-oxazinane ring structure at the 5-position of the benzamide core structure. CH4987655 exhibits slow dissociation from the MEK enzyme, remarkable in vivo antitumor efficacy both in mono- and combination therapy, desirable metabolic stability, and insignificant MEK inhibition in mouse brain, implying few CNS-related side effects in human. An excellent PK profile and clear target inhibition in PBMC were demonstrated in a healthy volunteer clinical study.

PubMed: 21316218
DOI: 10.1016/j.bmcl.2011.01.062

実験手法

X-RAY DIFFRACTION (2.8 Å)