The Pan-RAF–MEK Nondegrading Molecular Glue NST-628 Is a Potent and Brain-Penetrant Inhibitor of the RAS–MAPK Pathway - Potent brain-penetrant molecular glue for RAF–MEK signaling

Sep 22, 2026

Upload by Aria

Alterations in the RAS–MAPK cascade drive many solid tumors, and effective inhibition is constrained by toxicity and limited durable responses of existing therapies. NST-628 is a pan-RAF–MEK molecular glue that prevents RAF-driven MEK phosphorylation and activation, engaging all RAF isoforms while blocking RAF heterodimer formation. Cellular, biochemical, and structural studies support its distinct, durable RAF–MEK pathway suppression. High intrinsic permeability enables central nervous system activity and broad efficacy across cellular and patient-derived tumor models, including orthotopic intracranial settings.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Significance

Introduction

RAS–MAPK pathway alterations and clinical targeting

Limitations of current RAF and MEK inhibitors

Mechanisms of resistance and combination strategies

ReseaRch aRticle The Pan-RAF–MEK Nondegrading Molecular Glue NST-628 Is a Potent and Brain-Penetrant Inhibitor ofthe RAS–MAPK Pathway with Activity across Diverse RAS-and RAF-Driven Cancers Meagan B. Ryan1, Bradley Quade1, Natasha Schenk1, Zhong Fang1, Marshall Zingg1, Steven E. Cohen1, Brooke M. Swalm1, Chun Li1, Ayşegül Özen1, Chaoyang Ye1, Maria Stella Ritorto1, Xin Huang1, Arvin C. Dar2, Yongxin Han1, Klaus P. Hoeflich1, Michael Hale1, and Margit Hagel1 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. intRoduction Dysregulation of RAS–MAPK (RAS–RAF–MEK–ERK) pathway signaling is one of the most frequently occurring events in tumor development and has presented a promising and challenging clinical target in precision oncology. RAS (KRAS, NRAS, and HRAS) mutations occur in approximately 27% of cancers, with KRAS mutations occurring most frequently in pancreatic (95%), colorectal (50%), and lung tumors (30%), with RAF (ARAF, BRAF, and CRAF) mutations most frequently occurring in BRAF in 7% of tumors, primarily in melanoma (50%; refs. 1–3). Additional activating or loss-of-function mutations, such as mutation or loss of neurofibromin 1 (NF1) or mutations in receptor tyrosine kinases (RTK), also frequently occur in cancer and contribute to aberrant activation and dependency on the RAS–MAPK pathway for tumor growth and maintenance. Selective and potent inhibitors have been developed for every node of the RAS–RAF–MEK–ERK pathway, with varying degrees of success related to tolerability and durability of response clinically. Highly potent and selective ATP noncompetitive inhibitors of MEK1/2 and monomer selective (type I RAF) inhibitors of BRAF with potency in BRAF V600X (BRAF class I mutants) 1Nested Therapeutics, Cambridge, Massachusetts. 2Program in Chemical Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York. M.B. Ryan and B. Quade contributed equally to this article. Corresponding Authors: Margit Hagel, Nested Therapeutics, 1030 Massachusetts Avenue, Cambridge, MA 02138. E-mail: [mhagel@nestedtx.com](mhagel@nestedtx.com); Michael Hale, Nested Therapeutics, Cambridge, MA 02139. E-mail: [mhale@nestedtx.com](mhale@nestedtx.com); and Klaus Hoeflich, Nested Therapeutics, Cambridge, [MA 02139. E-mail: khoeflich@nestedtx.com](MA 02139. E-mail: khoeflich@nestedtx.com) Cancer Discov 2024;14:1190–205 doi: 10. 1158/2159-8290 . CD-24-0139 ThisopenaccessarticleisdistributedundertheCreative CommonsAttributionNonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.©2024 The Authors

FAQs

What is NST-628 and what pathway does it target?

NST-628 is a pan-RAF–MEK molecular glue that targets RAF–MEK signaling within the RAS–MAPK pathway by preventing MEK phosphorylation and activation by RAF.

How does NST-628 differ from existing RAF inhibitors?

NST-628 engages all RAF isoforms and prevents the formation of BRAF–CRAF heterodimers, representing a differentiated mechanism from current RAF inhibitors.

Why is NST-628 relevant to treating brain-involved tumors?

NST-628 has high intrinsic permeability into the brain, and it shows activity across models including orthotopic intracranial tumor settings.

Sep 22, 2026

Upload by Aria