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Crystal structure of KSR1/MEK1 complex heterotetramer with NST-628
Structural highlights
FunctionKSR1_HUMAN Scaffolding protein that is part of a multiprotein signaling complex. Promotes phosphorylation of Raf family members and activation of downstream MAP kinases. Promotes activation of MAPK1 and/or MAPK3, both in response to EGF and to cAMP. Does not have kinase activity by itself.[UniProtKB:Q61097] Publication Abstract from PubMedAlterations 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. 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.,Ryan MB, Quade B, Schenk N, Fang Z, Zingg M, Cohen SE, Swalm BM, Li C, Ozen A, Ye C, Ritorto MS, Huang X, Dar AC, Han Y, Hoeflich KP, Hale M, Hagel M Cancer Discov. 2024 Jul 1;14(7):1190-1205. doi: 10.1158/2159-8290.CD-24-0139. PMID:38588399[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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