5HD7

Dissecting Therapeutic Resistance to ERK Inhibition Rat Mutant SCH772984 in complex with (3R)-1-(2-oxo-2-{4-[4-(pyrimidin-2-yl)phenyl]piperazin-1-yl}ethyl)-N-[3-(pyridin-4-yl)-2H-indazol-5-yl]pyrrolidine-3-carboxamide

5HD7 の概要

• エントリーDOI: 10.2210/pdb5hd7/pdb
• 関連するPDBエントリー: 5HD4
• 分子名称: Mitogen-activated protein kinase 1, (3R)-1-(2-oxo-2-{4-[4-(pyrimidin-2-yl)phenyl]piperazin-1-yl}ethyl)-N-[3-(pyridin-4-yl)-2H-indazol-5-yl]pyrrolidine-3-carboxamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: transferase, serine/threonine-protein kinase, map kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Rattus norvegicus (Rat)
• 細胞内の位置: Cytoplasm, cytoskeleton, spindle : P63086
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43356.54

構造登録者

Jha, S.,Morris, E.J.,Hruza, A.,Mansueto, M.S.,Schroeder, G.,Arbanas, J.,McMasters, D.,Restaino, C.R.,Dayananth, R.,Black, S.,Elsen, N.L.,Mannarino, A.,Cooper, A.,Fawell, S.,Zawel, L.,Jayaraman, L.,Samatar, A.A. (登録日: 2016-01-04, 公開日: 2016-02-24, 最終更新日: 2024-03-06)

主引用文献

Jha, S.,Morris, E.J.,Hruza, A.,Mansueto, M.S.,Schroeder, G.K.,Arbanas, J.,McMasters, D.,Restaino, C.R.,Dayananth, P.,Black, S.,Elsen, N.L.,Mannarino, A.,Cooper, A.,Fawell, S.,Zawel, L.,Jayaraman, L.,Samatar, A.A.
Dissecting Therapeutic Resistance to ERK Inhibition.
Mol.Cancer Ther., 15:548-559, 2016

PubMed Abstract: The MAPK pathway is frequently activated in many human cancers, particularly melanomas. A single-nucleotide mutation in BRAF resulting in the substitution of glutamic acid for valine (V(600E)) causes constitutive activation of the downstream MAPK pathway. Selective BRAF and MEK inhibitor therapies have demonstrated remarkable antitumor responses in BRAF(V600) (E)-mutant melanoma patients. However, initial tumor shrinkage is transient and the vast majority of patients develop resistance. We previously reported that SCH772984, an ERK 1/2 inhibitor, effectively suppressed MAPK pathway signaling and cell proliferation in BRAF, MEK, and concurrent BRAF/MEK inhibitor-resistant tumor models. ERK inhibitors are currently being evaluated in clinical trials and, in anticipation of the likelihood of clinical resistance, we sought to prospectively model acquired resistance to SCH772984. Our data show that long-term exposure of cells to SCH772984 leads to acquired resistance, attributable to a mutation of glycine to aspartic acid (G(186D)) in the DFG motif of ERK1. Structural and biophysical studies demonstrated specific defects in SCH772984 binding to mutant ERK. Taken together, these studies describe the interaction of SCH772984 with ERK and identify a novel mechanism of ERK inhibitor resistance through mutation of a single residue within the DFG motif. Mol Cancer Ther; 15(4); 548-59. ©2016 AACR.

PubMed: 26832798
DOI: 10.1158/1535-7163.MCT-15-0172

実験手法

X-RAY DIFFRACTION (1.69 Å)