Reference Detail

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
NST-628	NST-628	2	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
NST-628		NST628\|NST 628		NST-628 stabilizes the RAF-MEK complex, which inhibits MEK/ERK/RSK phosphorylation and reactivation of the pathway, potentially leading to tumor growth inhibition (Mol Cancer Ther (2023) 22 (12_Supplement): A086, Mol Cancer Ther (2023) 22 (12_Supplement): A088).

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
NRAS Q61L	melanoma	predicted - sensitive	NST-628	Preclinical - Cell line xenograft	Actionable	In a preclinical study, NST-628 induced tumor regression in a melanoma cell line xenograft model harboring NRAS Q61L (Mol Cancer Ther (2023) 22 (12_Supplement): A088).	detail...