Abstract ND10: NST-628 is a novel, potent, fully brain-penetrant MAPK pathway molecular glue that inhibits RAS- and RAF-driven cancers

Abstract Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and are drivers for many cancers. Apart from approved mutation-selective inhibitors for BRAF Class I and KRAS G12C mutations, other mutations of RAS and RAF are not directly addressable by currently approved inhibitors and there is a need for therapeutic strategies having superior efficacy, durability and tolerability for the MAPK pathway. NST-628 is a potent pan-RAF-MEK molecular glue that prevents phosphorylation and activation of MEK by RAF. In this way, NST-628 overcomes the limitations of traditional RAS-MAPK inhibitors and drives deep, durable inhibition of the RAS-MAPK pathway. Cellular, biochemical, and structural analysis of RAF-MEK complexes show that NST-628 engages all isoforms of RAF and prevents the formation of BRAF-CRAF and BRAF-ARAF heterodimers, a differentiated mechanism from all current RAF-directed inhibitors. With its potent and durable inhibition of the RAF-MEK signaling complex, NST-628 demonstrates broad efficacy in cellular and patient-derived, in vivo tumor models harboring KRAS, NRAS, BRAF class II/III, and NF1 mutations. In addition, high intrinsic permeability across the blood-brain-barrier results in NST-628-mediated intracranial anti-tumor activity in orthotopic tumor models. Furthermore, NST-628 pharmacokinetic and metabolic profiles have been optimized for daily dosing in the clinic to maximize therapeutic index. Given its differentiated molecular mechanism, best-in-class drug-like properties, and superior safety profile in IND-enabling GLP studies, NST-628 is positioned to make an impact clinically to address unmet patient need. First-in-human trials of NST-628 have been initiated in early 2024 Citation Format: Meagan B. Ryan, Bradley Quade, Natasha Schenk, Zhong Fang, Marshall Zingg, Steven E. Cohen, Chun Li, Brooke M. Swalm, Aysegul Ozen, Chaoyang Ye, Maria Stella Ritorto, Xin Huang, Arvin C. Dar, Yongxin Han, Michael Hale, Margit Hagel, Klaus P. Hoeflich. NST-628 is a novel, potent, fully brain-penetrant MAPK pathway molecular glue that inhibits RAS- and RAF-driven cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr ND10.