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Ref Type Journal Article
PMID (34330842)
Authors Munck JM, Berdini V, Bevan L, Brothwood JL, Castro J, Courtin A, East C, Ferraldeschi R, Heightman TD, Hindley CJ, Kucia-Tran J, Lyons JF, Martins V, Muench S, Murray CW, Norton D, O'Reilly M, Reader M, Rees DC, Rich SJ, Richardson CJ, Shah AD, Stanczuk L, Thompson NT, Wilsher NE, Woolford AJ, Wallis NG
Title ASTX029, a Novel Dual-mechanism ERK Inhibitor, Modulates Both the Phosphorylation and Catalytic Activity of ERK.
Journal Molecular cancer therapeutics
Vol 20
Issue 10
Date 2021 10
URL
Abstract Text The MAPK signaling pathway is commonly upregulated in human cancers. As the primary downstream effector of the MAPK pathway, ERK is an attractive therapeutic target for the treatment of MAPK-activated cancers and for overcoming resistance to upstream inhibition. ASTX029 is a highly potent and selective dual-mechanism ERK inhibitor, discovered using fragment-based drug design. Because of its distinctive ERK-binding mode, ASTX029 inhibits both ERK catalytic activity and the phosphorylation of ERK itself by MEK, despite not directly inhibiting MEK activity. This dual mechanism was demonstrated in cell-free systems, as well as cell lines and xenograft tumor tissue, where the phosphorylation of both ERK and its substrate, ribosomal S6 kinase (RSK), were modulated on treatment with ASTX029. Markers of sensitivity were highlighted in a large cell panel, where ASTX029 preferentially inhibited the proliferation of MAPK-activated cell lines, including those with BRAF or RAS mutations. In vivo, significant antitumor activity was observed in MAPK-activated tumor xenograft models following oral treatment. ASTX029 also demonstrated activity in both in vitro and in vivo models of acquired resistance to MAPK pathway inhibitors. Overall, these findings highlight the therapeutic potential of a dual-mechanism ERK inhibitor such as ASTX029 for the treatment of MAPK-activated cancers, including those which have acquired resistance to inhibitors of upstream components of the MAPK pathway. ASTX029 is currently being evaluated in a first in human phase I-II clinical trial in patients with advanced solid tumors (NCT03520075).

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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
ASTX029 ASTX029 11 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
ASTX029 ASTX-029|ASTX 029 ERK Inhibitor (pan) 18 ERK1 Inhibitor 2 ERK2 Inhibitor 2 ASTX029 is an ERK1/2 inhibitor that prevents MAPK/ERK pathway activation, which may result in growth inhibition and tumor regression (PMID: 34330842).
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
BRAF V600D melanoma sensitive ASTX029 Preclinical - Cell culture Actionable In a preclinical study, ASTX029 treatment inhibited growth of a melanoma cell line harboring BRAF V600D in culture (PMID: 34330842). 34330842
BRAF V600E melanoma sensitive ASTX029 + Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, combination treatment with ASTX029 and Zelboraf (vemurafenib) resulted in decreased viability of melanoma cells harboring BRAF V600E compared to either agent alone in culture (PMID: 34330842). 34330842
NRAS G12D acute myeloid leukemia sensitive ASTX029 Preclinical - Cell culture Actionable In a preclinical study, acute myeloid leukemia cells harboring NRAS G12D were sensitive to treatment with ASTX029 in culture (PMID: 34330842). 34330842
FLT3 exon 14 ins acute myeloid leukemia sensitive ASTX029 Preclinical - Cell culture Actionable In a preclinical study, acute myeloid leukemia cell lines harboring FLT3-ITD mutations were sensitive to treatment with ASTX029 in culture (PMID: 34330842). 34330842
NRAS Q61L acute myeloid leukemia sensitive ASTX029 Preclinical - Cell culture Actionable In a preclinical study, acute myeloid leukemia cells harboring NRAS Q61L were sensitive to treatment with ASTX029 in culture (PMID: 34330842). 34330842
BRAF V600E melanoma sensitive ASTX029 Preclinical - Cell line xenograft Actionable In a preclinical study, ASTX029 treatment reduced Erk and Rsk phosphorylation, induced cell-cycle arrest, and inhibited growth of a melanoma cell line harboring BRAF V600E in culture and inhibited tumor growth in cell line xenograft models, and was also effective against cells with acquired resistance to Zelboraf (vemurafenib) or Koselugo (selumetinib) (PMID: 34330842). 34330842
NRAS G12D melanoma sensitive ASTX029 Preclinical - Cell culture Actionable In a preclinical study, ASTX029 treatment inhibited growth of a melanoma cell line harboring NRAS G12D in culture (PMID: 34330842). 34330842
NRAS Q61R melanoma sensitive ASTX029 Preclinical - Cell line xenograft Actionable In a preclinical study, ASTX029 treatment inhibited growth of melanoma cell lines harboring NRAS Q61R in culture, and inhibited tumor growth in cell line xenograft models (PMID: 34330842). 34330842
BRAF V600E colorectal adenocarcinoma sensitive ASTX029 Preclinical - Cell line xenograft Actionable In a preclinical study, ASTX029 treatment reduced Erk and Rsk phosphorylation and inhibited growth of colorectal adenocarcinoma cell lines harboring BRAF V600E in culture, and inhibited tumor growth and induced tumor regression in cell line xenograft models (PMID: 34330842). 34330842
NRAS G13D melanoma sensitive ASTX029 Preclinical - Cell culture Actionable In a preclinical study, ASTX029 treatment inhibited growth of a melanoma cell line harboring NRAS G13D in culture (PMID: 34330842). 34330842
NRAS Q61K melanoma sensitive ASTX029 Preclinical - Pdx Actionable In a preclinical study, ASTX029 treatment inhibited growth of melanoma cell lines harboring NRAS Q61K in culture, and inhibited tumor growth in a patient-derived xenograft (PDX) model of melanoma harboring NRAS Q61K (PMID: 34330842). 34330842
BRAF V600E NRAS Q61K melanoma sensitive ASTX029 Preclinical - Cell culture Actionable In a preclinical study, ASTX029 treatment reduced Erk and Rsk phosphorylation and inhibited growth of a melanoma cell line harboring BRAF V600E and expressing NRAS Q61K in culture (PMID: 34330842). 34330842