{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Ryan MB"],"funding":["NCI NIH HHS"],"pagination":["1190-1205"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11215411"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["14(7)"],"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."],"journal":["Cancer discovery"],"pubmed_title":["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."],"pmcid":["PMC11215411"],"funding_grant_id":["P30 CA008748","R01 CA227636"],"pubmed_authors":["Ozen A","Ryan MB","Hagel M","Li C","Quade B","Ye C","Hoeflich KP","Han Y","Zingg M","Cohen SE","Fang Z","Huang X","Dar AC","Hale M","Ritorto MS","Swalm BM","Schenk N"],"additional_accession":[]},"is_claimable":false,"name":"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.","description":"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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Jul","modification":"2026-07-04T03:19:41.914Z","creation":"2025-04-07T02:10:17.574Z"},"accession":"S-EPMC11215411","cross_references":{"pubmed":["38588399"],"doi":["10.1158/2159-8290.CD-24-0139"]}}