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TitleThe 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.
Journal, issue, pagesCancer Discov, Vol. 14, Issue 7, Page 1190-1205, Year 2024
Publish dateJul 1, 2024
AuthorsMeagan B Ryan / Bradley Quade / Natasha Schenk / Zhong Fang / Marshall Zingg / Steven E Cohen / Brooke M Swalm / Chun Li / Ayşegül Özen / Chaoyang Ye / Maria Stella Ritorto / Xin Huang / Arvin C Dar / Yongxin Han / Klaus P Hoeflich / Michael Hale / Margit Hagel /
PubMed AbstractAlterations 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 ...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.
External linksCancer Discov / PubMed:38588399 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.07 - 4.36 Å
Structure data

43931

9axa

EMDB-43931, PDB-9axa:
CryoEM structure of activated CRAF/MEK/14-3-3 complex with NST-628
Method: EM (single particle) / Resolution: 4.36 Å

43932

9axc

EMDB-43932, PDB-9axc:
Activated CRAF/MEK heterotetramer from focused refinement of CRAF/MEK/14-3-3 complex
Method: EM (single particle) / Resolution: 4.16 Å

PDB-9axh:
Crystal structure of KSR1/MEK1 complex heterotetramer with NST-628
Method: X-RAY DIFFRACTION / Resolution: 2.81 Å

PDB-9axm:
Crystal structure of ARAF/MEK1 complex with NST-628 and a RAF dimer
Method: X-RAY DIFFRACTION / Resolution: 2.42 Å

PDB-9axx:
Crystal structure of BRAF/MEK1 complex with NST-628 and an active RAF dimer
Method: X-RAY DIFFRACTION / Resolution: 2.07 Å

PDB-9axy:
Crystal structure of BRAF/MEK complex with NST-628 and inactive RAF
Method: X-RAY DIFFRACTION / Resolution: 3.6 Å

PDB-9ay7:
Crystal structure of CRAF/MEK1 complex with NST-628 and inactive RAF
Method: X-RAY DIFFRACTION / Resolution: 2.41 Å

PDB-9aya:
Crystal structure of CRAF/MEK complex with NST-628 and active RAF dimer
Method: X-RAY DIFFRACTION / Resolution: 2.59 Å

Chemicals

PDB-1ahe:
ASPARTATE AMINOTRANSFERASE HEXAMUTANT

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

ChemComp-MG:
Unknown entry

ChemComp-EDO:
1,2-ETHANEDIOL

ChemComp-CL:
Unknown entry

ChemComp-HOH:
WATER

ChemComp-GOL:
GLYCEROL

ChemComp-TRS:
2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / pH buffer*YM

ChemComp-NI:
NICKEL (II) ION

ChemComp-ACT:
ACETATE ION

Source
  • homo sapiens (human)
KeywordsTRANSFERASE / Inhibitor / complex / SIGNALING PROTEIN

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