American Association for Cancer Research
15357163mct200909-sup-254268_3_supp_7101656_qs6gg6.pdf (657.79 kB)

Supplementary Tables 1-6 from ASTX029, a Novel Dual-mechanism ERK Inhibitor, Modulates Both the Phosphorylation and Catalytic Activity of ERK

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journal contribution
posted on 2023-04-03, 18:27 authored by Joanne M. Munck, Valerio Berdini, Luke Bevan, Jessica L. Brothwood, Juan Castro, Aurélie Courtin, Charlotte East, Roberta Ferraldeschi, Tom D. Heightman, Christopher J. Hindley, Justyna Kucia-Tran, John F. Lyons, Vanessa Martins, Sandra Muench, Christopher W. Murray, David Norton, Marc O'Reilly, Michael Reader, David C. Rees, Sharna J. Rich, Caroline J. Richardson, Alpesh D. Shah, Lukas Stanczuk, Neil T. Thompson, Nicola E. Wilsher, Alison J.-A. Woolford, Nicola G. Wallis

Supplementary tables 1-6 summarise the kinase panel screen data (1) mouse PK parameters (2) and further details of the anti-tumour activity (5) conferred by ASTX029, plus details of cell lines used in this study (3 and 4) and further details of the effects of ASTX029 and other MAPK inhibitors in models of MAPK resistance (6).



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).