4AN9

Crystal structures of human MEK1 with carboxamide-based allosteric inhibitor XL518 (GDC-0973), or related analogs.

4AN9 の概要

• エントリーDOI: 10.2210/pdb4an9/pdb
• 関連するPDBエントリー: 1S9J 4AN2 4AN3 4ANB
• 分子名称: DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: transferase, map2k1, atp-binding, allosteric inhibition
• 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: 34592.42

構造登録者

Rice, K.D.,Aay, N.,Anand, N.K.,Blazey, C.M.,Bowles, O.J.,Bussenius, J.,Costanzo, S.,Curtis, J.K.,Defina, S.C.,Dubenko, L.,Engst, S.,Joshi, A.A.,Kennedy, A.R.,Kim, A.I.,Koltun, E.S.,Lougheed, J.C.,Manalo, J.C.L.,Martini, J.F.,Nuss, J.M.,Peto, C.J.,Tsang, T.H.,Yu, P.,Johnston, S. (登録日: 2012-03-16, 公開日: 2012-12-19, 最終更新日: 2024-05-01)

主引用文献

Rice, K.D.,Aay, N.,Anand, N.K.,Blazey, C.M.,Bowles, O.J.,Bussenius, J.,Costanzo, S.,Curtis, J.K.,Defina, S.C.,Dubenko, L.,Engst, S.,Joshi, A.A.,Kennedy, A.R.,Kim, A.I.,Koltun, E.S.,Lougheed, J.C.,Manalo, J.C.L.,Martini, J.F.,Nuss, J.M.,Peto, C.J.,Tsang, T.H.,Yu, P.,Johnston, S.
Novel Carboxamide-Based Allosteric Mek Inhibitors: Discovery and Optimization Efforts Toward Xl518 (Gdc-0973)
Acs Med.Chem.Lett., 3:416-, 2012

PubMed Abstract: The ERK/MAP kinase cascade is a key mechanism subject to dysregulation in cancer and is constitutively activated or highly upregulated in many tumor types. Mutations associated with upstream pathway components RAS and Raf occur frequently and contribute to the oncogenic phenotype through activation of MEK and then ERK. Inhibitors of MEK have been shown to effectively block upregulated ERK/MAPK signaling in a range of cancer cell lines and have further demonstrated early evidence of efficacy in the clinic for the treatment of cancer. Guided by structural insight, a strategy aimed at the identification of an optimal diphenylamine-based MEK inhibitor with an improved metabolism and safety profile versus PD-0325901 led to the discovery of development candidate 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol (XL518, GDC-0973) (1). XL518 exhibits robust in vitro and in vivo potency and efficacy in preclinical models with sustained duration of action and is currently in early stage clinical trials.

PubMed: 24900486
DOI: 10.1021/ML300049D

実験手法

X-RAY DIFFRACTION (2.8 Å)