6RQ4

Inhibitor of ERK2

Summary for 6RQ4

• Entry DOI: 10.2210/pdb6rq4/pdb
• Descriptor: Mitogen-activated protein kinase 1, SULFATE ION, 6,6-dimethyl-2-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5-(2-morpholin-4-ylethyl)thieno[2,3-c]pyrrol-4-one, ... (4 entities in total)
• Functional Keywords: protein kinase atp-binding site serine/threonine kinase, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 43101.54

Authors

O'Reilly, M. (deposition date: 2019-05-15, release date: 2019-12-04, Last modification date: 2024-11-06)

Primary citation

Kidger, A.M.,Munck, J.M.,Saini, H.K.,Balmanno, K.,Minihane, E.,Courtin, A.,Graham, B.,O'Reilly, M.,Odle, R.,Cook, S.J.
Dual-Mechanism ERK1/2 Inhibitors Exploit a Distinct Binding Mode to Block Phosphorylation and Nuclear Accumulation of ERK1/2.
Mol.Cancer Ther., 19:525-539, 2020

PubMed Abstract: The RAS-regulated RAF-MEK1/2-ERK1/2 signaling pathway is frequently deregulated in cancer due to activating mutations of growth factor receptors, RAS or BRAF. Both RAF and MEK1/2 inhibitors are clinically approved and various ERK1/2 inhibitors (ERKi) are currently undergoing clinical trials. To date, ERKi display two distinct mechanisms of action (MoA): catalytic ERKi solely inhibit ERK1/2 catalytic activity, whereas dual mechanism ERKi additionally prevents the activating phosphorylation of ERK1/2 at its T-E-Y motif by MEK1/2. These differences may impart significant differences in biological activity because T-E-Y phosphorylation is the signal for nuclear entry of ERK1/2, allowing them to access many key transcription factor targets. Here, we characterized the MoA of five ERKi and examined their functional consequences in terms of ERK1/2 signaling, gene expression, and antiproliferative efficacy. We demonstrate that catalytic ERKi promote a striking nuclear accumulation of p-ERK1/2 in KRAS-mutant cell lines. In contrast, dual-mechanism ERKi exploits a distinct binding mode to block ERK1/2 phosphorylation by MEK1/2, exhibit superior potency, and prevent the nuclear accumulation of ERK1/2. Consequently, dual-mechanism ERKi exhibit more durable pathway inhibition and enhanced suppression of ERK1/2-dependent gene expression compared with catalytic ERKi, resulting in increased efficacy across BRAF- and RAS-mutant cell lines.

PubMed: 31748345
DOI: 10.1158/1535-7163.MCT-19-0505

Experimental method

X-RAY DIFFRACTION (1.96 Å)