ArticleBiochemistry2015
Slow inhibition and conformation selective properties of extracellular signal-regulated kinase 1 and 2 inhibitors.
Article in Biochemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
20 citing papers in PubMed, 44 citations in OpenAlex.
- Protein-ligand binding kinetics are primarily controlled by the protein, not the ligand.bioRxiv : the preprint server for biology · 2026Article
- Advances in ERK1/2 inhibition: a medicinal chemistry perspective on structure and regulation.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- KSR1 Mediates Small Cell Lung Carcinoma Tumor Initiation and Cisplatin Resistance.Molecular cancer research : MCR · 2025Article
- Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2.eLife · 2024Article
- Activation Loop Plasticity and Active Site Coupling in the MAP Kinase, ERK2.Journal of molecular biology · 2023Article
- Conformation Selection by ATP-competitive Inhibitors and Allosteric Communication in ERK2.bioRxiv : the preprint server for biology · 2023Article
- ERK Inhibition Promotes Engraftment of Allografts by Reprogramming T-Cell Metabolism.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Identification of cell type-specific correlations between ERK activity and cell viability upon treatment with ERK1/2 inhibitors.The Journal of biological chemistry · 2022Article
- Dynamic equilibria in protein kinases.Current opinion in structural biology · 2021Review
- Activation Loop Dynamics Are Coupled to Core Motions in Extracellular Signal-Regulated Kinase-2.Biochemistry · 2020Article
- Activation loop dynamics are controlled by conformation-selective inhibitors of ERK2.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Article
- Specificity of Phosphorylation Responses to Mitogen Activated Protein (MAP) Kinase Pathway Inhibitors in Melanoma Cells.Molecular & cellular proteomics : MCP · 2018Article
- Isoform-selective activity-based profiling of ERK signaling.Chemical science · 2018Article
- Mechanistic enzymology in drug discovery: a fresh perspective.Nature reviews. Drug discovery · 2018Review
- Drug-Target Kinetics in Drug Discovery.ACS chemical neuroscience · 2018Article
- Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade.F1000Research · 2016Article
- TargetingTrends in cancer · 2015Article
- Dynamics of protein kinases: insights from nuclear magnetic resonance.Accounts of chemical research · 2015Article
- Research progress of the role and mechanism of extracellular signal-regulated protein kinase 5 (ERK5) pathway in pathological pain.Journal of Zhejiang University. Science. BReview
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The mitogen-activated protein (MAP) kinase pathway is a target for anticancer therapy, validated using inhibitors of B-Raf and MAP kinase kinase (MKK) 1 and 2. Clinical outcomes show a high frequency of acquired resistance in patient tumors, involving upregulation of activity of the MAP kinase, extracellular signal-regulated kinase (ERK) 1 and 2. Thus, inhibitors for ERK1/2 are potentially important for targeted therapeutics against cancer. The structures and potencies of different ERK inhibitors have been published, but their kinetic mechanisms have not been characterized. Here we perform enzyme kinetic studies on six representative ERK inhibitors, with potencies varying from 100 pM to 20 μM. Compounds with significant biological activity (IC50 < 100 nM) that inhibit in the subnanomolar range (Vertex-11e and SCH772984) display slow-onset inhibition and represent the first inhibitors of ERK2 known to demonstrate slow dissociation rate constants (values of 0.2 and 1.1 h(-1), respectively). Furthermore, we demonstrate using kinetic competition assays that Vertex-11e binds with differing affinities to ERK2 in its inactive, unphosphorylated and active, phosphorylated forms. Finally, two-dimensional heteronuclear multiple-quantum correlation nuclear magnetic resonance experiments reveal that distinct conformational states are formed in complexes of Vertex-11e with inactive and active ERK2. Importantly, two conformers interconvert in equilibrium in the active ERK2 apoenzyme, but Vertex-11e strongly shifts the equilibrium completely to one conformer. Thus, a high-affinity, slow dissociation inhibitor stabilizes different enzyme conformations depending on the activity state of ERK2 and reveals properties of conformational selection toward the active kinase.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.