9AXC

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

This is a non-PDB format compatible entry.

Summary for 9AXC

• Entry DOI: 10.2210/pdb9axc/pdb
• EMDB information: 43932
• Descriptor: 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)
• Functional Keywords: inhibitor, complex, signaling protein, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 217451.88

Authors

Quade, B.,Cohen, S.E.,Huang, X. (deposition date: 2024-03-06, release date: 2024-04-17, Last modification date: 2024-07-10)

Primary citation

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 are a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents the 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 analyses of RAF-MEK complexes show that NST-628 engages all isoforms of RAF and 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 areas of unmet patient need. Significance: This study introduces NST-628, a molecular glue having differentiated mechanism and drug-like properties. NST-628 treatment leads to broad efficacy with high tolerability and central nervous system activity across multiple RAS- and RAF-driven tumor models. NST-628 has the potential to provide transformative clinical benefits as both monotherapy and vertical combination anchor.

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

Experimental method

ELECTRON MICROSCOPY (4.16 Å)