ASTX029, a Novel Dual-mechanism ERK Inhibitor, Modulates Both the Phosphorylation and Catalytic Activity of ERK.

Autor:	Munck JM; Astex Pharmaceuticals, Cambridge, United Kingdom. nicola.wallis@astx.com joanne.munck@astx.com., Berdini V; Astex Pharmaceuticals, Cambridge, United Kingdom., Bevan L; Astex Pharmaceuticals, Cambridge, United Kingdom., Brothwood JL; Astex Pharmaceuticals, Cambridge, United Kingdom., Castro J; Astex Pharmaceuticals, Cambridge, United Kingdom., Courtin A; Astex Pharmaceuticals, Cambridge, United Kingdom., East C; Astex Pharmaceuticals, Cambridge, United Kingdom., Ferraldeschi R; Astex Pharmaceuticals, Cambridge, United Kingdom., Heightman TD; Astex Pharmaceuticals, Cambridge, United Kingdom., Hindley CJ; Astex Pharmaceuticals, Cambridge, United Kingdom., Kucia-Tran J; Astex Pharmaceuticals, Cambridge, United Kingdom., Lyons JF; Astex Pharmaceuticals, Cambridge, United Kingdom., Martins V; Astex Pharmaceuticals, Cambridge, United Kingdom., Muench S; Astex Pharmaceuticals, Cambridge, United Kingdom., Murray CW; Astex Pharmaceuticals, Cambridge, United Kingdom., Norton D; Astex Pharmaceuticals, Cambridge, United Kingdom., O'Reilly M; Astex Pharmaceuticals, Cambridge, United Kingdom., Reader M; Astex Pharmaceuticals, Cambridge, United Kingdom., Rees DC; Astex Pharmaceuticals, Cambridge, United Kingdom., Rich SJ; Astex Pharmaceuticals, Cambridge, United Kingdom., Richardson CJ; Astex Pharmaceuticals, Cambridge, United Kingdom., Shah AD; Astex Pharmaceuticals, Cambridge, United Kingdom., Stanczuk L; Astex Pharmaceuticals, Cambridge, United Kingdom., Thompson NT; Astex Pharmaceuticals, Cambridge, United Kingdom., Wilsher NE; Astex Pharmaceuticals, Cambridge, United Kingdom., Woolford AJ; Astex Pharmaceuticals, Cambridge, United Kingdom., Wallis NG; Astex Pharmaceuticals, Cambridge, United Kingdom. nicola.wallis@astx.com joanne.munck@astx.com.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2021 Oct; Vol. 20 (10), pp. 1757-1768. Date of Electronic Publication: 2021 Jul 30.
DOI:	10.1158/1535-7163.MCT-20-0909
Abstrakt:	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). (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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