Reference Detail

Ref Type

Journal Article

PMID

(38588399)

Authors

Ryan MB, Quade B, Schenk N, Fang Z, Zingg M, Cohen SE, Swalm BM, Li C, Özen A, Ye C, Ritorto MS, Huang X, Dar AC, Han Y, Hoeflich KP, Hale M, Hagel M

Title

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	14	7	2024 Jul 01	1190-1205	Cancer Discov

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
NST-628	NST-628	6	1

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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
NST-628		NST628\|NST 628	MEK inhibitor (Pan) 27 RAF Inhibitor (Pan) 29	NST-628 stabilizes the RAF-MEK complex, which inhibits MEK/ERK/RSK phosphorylation and reactivation of the pathway, potentially leading to tumor growth inhibition (PMID: 38588399).

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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
BRAF	G466A	missense	unknown	BRAF G466A (also reported as G465A) lies within the protein kinase domain of the Braf protein (UniProt.org). The functional effect of G466A (also reported as G465A) is conflicting as it demonstrates both intermediate Braf kinase activity (PMID: 15035987) and low Braf kinase activity (PMID: 28783719), leads to Ras-dependent activation of downstream Erk in cell culture (PMID: 28783719), in one of two cell lines increased cell proliferation and cell viability compared to wild-type Braf (PMID: 29533785), and results in decreased interaction with Mek in an in vitro assay (PMID: 38588399).

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF D594E HRAS Q61L	melanoma	sensitive	NST-628	Preclinical - Pdx	Actionable	In a preclinical study, NST-628 treatment resulted in an overall response rate of 69.5% in a panel of patient-derived xenograft (PDX) models of solid tumors harboring RAS-MAPK pathway alterations, including a response in a melanoma patient-derived xenograft (PDX) model harboring BRAF D594E and HRAS Q61L (PMID: 38588399).	38588399
BRAF D594N	lung adenocarcinoma	predicted - sensitive	NST-628	Preclinical - Pdx	Actionable	In a preclinical study, NST-628 treatment resulted in an overall response rate of 69.5% in a panel of patient-derived xenograft (PDX) models of solid tumors harboring RAS-MAPK pathway alterations, including 1 response out of 2 lung adenocarcinoma patient-derived xenograft (PDX) models harboring BRAF D594N (PMID: 38588399).	38588399
BRAF G469A	lung sarcomatoid carcinoma	sensitive	NST-628	Preclinical - Pdx	Actionable	In a preclinical study, NST-628 treatment resulted in an overall response rate of 69.5% in a panel of patient-derived xenograft (PDX) models of solid tumors harboring RAS-MAPK pathway alterations, including a response in a lung sarcomatoid carcinoma patient-derived xenograft (PDX) model harboring BRAF G469A (PMID: 38588399).	38588399
BRAF G469E NRAS G13V	melanoma	sensitive	NST-628	Preclinical - Pdx	Actionable	In a preclinical study, NST-628 treatment resulted in an overall response rate of 69.5% in a panel of patient-derived xenograft (PDX) models of solid tumors harboring RAS-MAPK pathway alterations, including a response in a melanoma patient-derived xenograft (PDX) model harboring BRAF G469E and NRAS G13V (PMID: 38588399).	38588399
NRAS Q61L	melanoma	sensitive	NST-628	Preclinical - Cell line xenograft	Actionable	In a preclinical study, NST-628 inhibited viability of a melanoma cancer cell line harboring NRAS Q61L in culture and inhibited tumor growth and induced tumor regression in a cell line xenograft model (PMID: 38588399).	38588399
NRAS Q61R	melanoma	sensitive	NST-628	Preclinical - Cell line xenograft	Actionable	In a preclinical study, NST-628 inhibited viability of a melanoma cancer cell line harboring NRAS Q61R in culture and induced tumor regression in an intracranial cell line xenograft model (PMID: 38588399).	38588399

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