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

Alterations in the RAS-MAPK signaling pathway are prevalent in various solid tumors and play a significant role in cancer progression. NST-628 is a powerful pan-RAF-MEK molecular glue that inhibits the phosphorylation and activation of MEK by RAF, addressing the limitations of conventional RAS-MAPK inhibitors and resulting in sustained, deep inhibition of the pathway. Our cellular, biochemical, and structural analyses of RAF-MEK complexes demonstrate that NST-628 interacts with all RAF isoforms and prevents the formation of BRAF-CRAF heterodimers, distinguishing it from existing RAF inhibitors. With its potent and lasting inhibition of the RAF-MEK signaling complex, along with high intrinsic permeability to the brain, NST-628 shows broad efficacy in cellular models and patient-derived tumor models with diverse MAPK pathway alterations, including orthotopic intracranial models. Due to its unique functional and pharmacokinetic profiles compared to prior therapies, NST-628 is poised to address significant clinical needs.

Significance: This study presents NST-628 as a molecular glue with a distinct mechanism and favorable drug-like properties. Treatment with NST-628 demonstrates broad efficacy and high tolerability, along with central nervous system activity across multiple RAS- and RAF-driven tumor models. NST-628 holds the potential for transformative clinical benefits as both a standalone treatment and a foundational component in combination therapies.