4ZZO

Human ERK2 in complex with an irreversible inhibitor

4ZZO の概要

• エントリーDOI: 10.2210/pdb4zzo/pdb
• 関連するPDBエントリー: 4ZZM 4ZZN
• 分子名称: MITOGEN-ACTIVATED PROTEIN KINASE 1, SULFATE ION, N-[2-[[5-chloranyl-2-(oxan-4-ylamino)pyrimidin-4-yl]amino]phenyl]propanamide, ... (4 entities in total)
• 機能のキーワード: transferase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Cytoplasm, cytoskeleton, spindle : P28482
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41263.88

構造登録者

Ward, R.A.,Colclough, N.,Challinor, M.,Debreczeni, J.E.,Eckersley, K.,Fairley, G.,Feron, L.,Flemington, V.,Graham, M.A.,Greenwood, R.,Hopcroft, P.,Howard, T.D.,James, M.,Jones, C.D.,Jones, C.R.,Renshaw, J.,Roberts, K.,Snow, L.,Tonge, M.,Yeung, K. (登録日: 2015-04-10, 公開日: 2015-05-27, 最終更新日: 2024-11-06)

主引用文献

Ward, R.A.,Colclough, N.,Challinor, M.,Debreczeni, J.,Eckersley, K.,Fairley, G.,Feron, L.,Flemington, V.,Graham, M.A.,Greenwood, R.,Hopcroft, P.,Howard, T.D.,James, M.,Jones, C.D.,Jones, C.R.,Renshaw, J.,Roberts, K.,Snow, L.,Tonge, M.,Yeung, K.
Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of Erk1/2.
J.Med.Chem., 58:4790-, 2015

PubMed Abstract: The RAS/RAF/MEK/ERK signaling pathway has been targeted with a number of small molecule inhibitors in oncology clinical development across multiple disease indications. Importantly, cell lines with acquired resistance to B-RAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition by small molecule inhibitors. There are a number of selective, noncovalent ERK1/2 inhibitors reported along with the promiscuous hypothemycin (and related analogues) that act via a covalent mechanism of action. This article reports the identification of multiple series of highly selective covalent ERK1/2 inhibitors informed by structure-based drug design (SBDD). As a starting point for these covalent inhibitors, reported ERK1/2 inhibitors and a chemical series identified via high-throughput screening were exploited. These approaches resulted in the identification of selective covalent tool compounds for potential in vitro and in vivo studies to assess the risks and or benefits of targeting this pathway through such a mechanism of action.

PubMed: 25977981
DOI: 10.1021/ACS.JMEDCHEM.5B00466

実験手法

X-RAY DIFFRACTION (1.63 Å)