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Ref Type abstract
PMID
Authors Meagan B Ryan; Natasha Schenk; Marshall Zingg; Matthew Koehler; Brooke Swalm; Bradley Quade; Chaoyang Ye; Arvin C Dar; Yongxin Han; Klaus P Hoeflich; Michael R Hale; Margit Hagel
Title Abstract A088: NST-628 is a potent, best-in-class MAPK pathway molecular glue that inhibits RAS- and RAF-driven cancers
Journal Vol Issue Date Pages Journal Short Title
22 12_supplement 2023 Mol Cancer Ther
URL https://aacrjournals.org/mct/article/22/12_Supplement/A088/730458
Abstract Text Alterations in the RAS/RAF/MEK/ERK signaling cascade are common across multiple solid tumor types and aberrant signaling of the pathway is a driver for RAS- and RAF-driven 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 inhibitors with superior efficacy, durability and tolerability for the MAPK pathway in RAS- and RAF-driven cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents phosphorylation and activation of MEK by RAF, leading to deep durable inhibition of MEK kinase activity and downstream ERK signaling. In a MEK1 immunoprecipitation assay, NST-628 treatment glues ARAF, BRAF, and CRAF with unphosphorylated MEK1, stabilizing an inactive RAF-MEK complex and deeply inhibiting phospho-ERK signaling. In an unbiased cell line panel screen (550 models), NST-628 demonstrates efficacy across multiple tumor types with RAS-MAPK alterations, including melanoma, lung, and pancreatic models. NST-628 is broadly efficacious in models with BRAF Class II/III mutations, KRAS-mutations (G12C, G12D, G12V, G12R, Q61H), and NRAS-mutations (Q61x, G12x) as well as showing anti-proliferative effects in NF1-mutant/deficient models. Cell lines with NRAS Q61 mutations were particularly sensitive to NST-628 inhibition (GI50 average=150 nM). In vivo, NST-628 has a balanced metabolic profile and predicted half-life and exposure in humans is compatible with low dose daily dosing. NST-628 (3-5 mg/kg QD treatment) led to tumor regressions in HCT116 (KRAS G13D colorectal) and IPC-298 (NRAS Q61L melanoma) xenograft models, 53% and 38% respectively, correlating to inhibition of both phospho-MEK and phospho-ERK in tumors. In comparison to the MEK inhibitor trametinib, NST-628 led to deeper tumor responses and on target pathway inhibition in both models as well as significantly greater tolerability as measured by body weight. In a mini-mouse trial utilizing patient derive xenograft (PDX) tumors harboring NF1, KRAS G12D/R, BRAF Class II/III, and NRAS Q61x mutations, NST-628 (3 mg/kg QD) dosing demonstrates broad anti-tumor responses across melanoma, lung, pancreatic, glioma, and ovarian models. These data collectively, together with the predicted effective human half-life of NST-628 being consistent with daily dosing, support best-in-class potential for NST-628 and initiation of clinical trials in patients with solid tumors harboring RAS- and RAF-mutations is planned.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References