7AUV

The structure of ERK2 in complex with dual inhibitor ASTX029

Summary for 7AUV

• Entry DOI: 10.2210/pdb7auv/pdb
• Descriptor: Mitogen-activated protein kinase 1, SULFATE ION, DIMETHYL SULFOXIDE, ... (5 entities in total)
• Functional Keywords: mitogen activated kinase atp binding protein phosphorylation serine/threonine protein kinase, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 43502.28

Authors

O'Reilly, M. (deposition date: 2020-11-03, release date: 2021-10-06, Last modification date: 2024-11-06)

Primary citation

Munck, J.M.,Berdini, V.,Bevan, L.,Brothwood, J.L.,Castro, J.,Courtin, A.,East, C.,Ferraldeschi, R.,Heightman, T.D.,Hindley, C.J.,Kucia-Tran, J.,Lyons, J.F.,Martins, V.,Muench, S.,Murray, C.W.,Norton, D.,O'Reilly, M.,Reader, M.,Rees, D.C.,Rich, S.J.,Richardson, C.J.,Shah, A.D.,Stanczuk, L.,Thompson, N.T.,Wilsher, N.E.,Woolford, A.J.,Wallis, N.G.
ASTX029, a Novel Dual-mechanism ERK Inhibitor, Modulates Both the Phosphorylation and Catalytic Activity of ERK.
Mol.Cancer Ther., 20:1757-1768, 2021

PubMed Abstract: 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 or mutations. , significant antitumor activity was observed in MAPK-activated tumor xenograft models following oral treatment. ASTX029 also demonstrated activity in both and 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).

PubMed: 34330842
DOI: 10.1158/1535-7163.MCT-20-0909

Experimental method

X-RAY DIFFRACTION (1.76 Å)