9AXC

Activated CRAF/MEK heterotetramer from focused refinement of CRAF/MEK/14-3-3 complex

これはPDB形式変換不可エントリーです。

9AXC の概要

• エントリーDOI: 10.2210/pdb9axc/pdb
• EMDBエントリー: 43932
• 分子名称: GST26/CRAF chimera, Dual specificity mitogen-activated protein kinase kinase 1, N-[3-fluoro-4-({7-[(3-fluoropyridin-2-yl)oxy]-4-methyl-2-oxo-2H-1-benzopyran-3-yl}methyl)pyridin-2-yl]-N'-methylsulfuric diamide (3 entities in total)
• 機能のキーワード: inhibitor, complex, signaling protein, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 217451.88

構造登録者

Quade, B.,Cohen, S.E.,Huang, X. (登録日: 2024-03-06, 公開日: 2024-04-17, 最終更新日: 2024-07-10)

主引用文献

Ryan, M.B.,Quade, B.,Schenk, N.,Fang, Z.,Zingg, M.,Cohen, S.E.,Swalm, B.M.,Li, C.,Ozen, A.,Ye, C.,Ritorto, M.S.,Huang, X.,Dar, A.C.,Han, Y.,Hoeflich, K.P.,Hale, M.,Hagel, M.
The Pan-RAF-MEK Nondegrading Molecular Glue NST-628 Is a Potent and Brain-Penetrant Inhibitor of the RAS-MAPK Pathway with Activity across Diverse RAS- and RAF-Driven Cancers.
Cancer Discov, 14:1190-1205, 2024

PubMed Abstract: Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and is a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS-MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analysis of RAF-MEK complexes show that NST-628 engages all isoforms of RAFand prevents the formation of BRAF-CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors. With a potent and durable inhibition of the RAF-MEK signaling complex as well as high intrinsic permeability into the brain, NST-628 demonstrates broad efficacy in cellular and patient-derived tumor models harboring diverse MAPK pathway alterations, including orthotopic intracranial models. Given its functional and pharmacokinetic mechanisms that are differentiated from previous therapies , NST-628 is positioned to make an impact clinically in an areas of unmet patient need.

PubMed: 38588399
DOI: 10.1158/2159-8290.CD-24-0139

実験手法

ELECTRON MICROSCOPY (4.16 Å)