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Title | The pan-RAF-MEK non degrading 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. |
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Journal, issue, pages | Cancer Discov, Year 2024 |
Publish date | Apr 8, 2024 |
Authors | Meagan B Ryan / Bradley Quade / Natasha Schenk / Zhong Fang / Marshall Zingg / Steven E Cohen / Brooke M Swalm / Chun Li / Aysegul Ozen / Chaoyang Ye / Maria Stella Ritorto / Xin Huang / Arvin C Dar / Yongxin Han / Klaus P Hoeflich / Michael Hale / Margit Hagel / |
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 ...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. |
External links | Cancer Discov / PubMed:38588399 |
Methods | EM (single particle) / X-ray diffraction |
Resolution | 2.07 - 4.36 Å |
Structure data | EMDB-43931, PDB-9axa: EMDB-43932, PDB-9axc: PDB-9axh: PDB-9axm: PDB-9axx: PDB-9axy: PDB-9ay7: PDB-9aya: |
Chemicals | PDB-1ahe: ChemComp-ANP: ChemComp-MG: ChemComp-EDO: ChemComp-CL: ChemComp-HOH: ChemComp-GOL: ChemComp-TRS: ChemComp-NI: ChemComp-ACT: |
Source |
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Keywords | TRANSFERASE / Inhibitor / complex / SIGNALING PROTEIN |