ArticleNature chemical biology2014
A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics.
Article in Nature chemical biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 128 papers.
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Who cites it
128 citing papers in PubMed.
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- Activity of Direct KRAS(G12C) Inhibitors in Preclinical Models of Pediatric Cancer.Molecular cancer therapeutics · 2026Article
- Anti-Adipogenic Effects ofInternational journal of molecular sciences · 2026Article
- mTORC1 and nuclear ERK spatially control translation in cardiomyocytes through 4EBP1 phosphorylation.Science signaling · 2026Article
- The food additive 4-hexylresorcinol impairs intestinal stem cell function and exacerbates inflammatory bowel disease in Drosophila melanogaster via suppression of mapk signaling pathway.Cellular and molecular life sciences : CMLS · 2026Article
- Mitochondrial dynamics and cancer: mechanisms and targeted therapy.Cell biology and toxicology · 2026Review
- Altered residence time as a cause of drug resistance.Current opinion in structural biology · 2026Review
- Location-biased β-arrestin conformations direct GPCR signaling.Science signaling · 2026Article
- A green tandem cyclization approach to substituted 2-aminothiazolesRSC advances · 2026Article
- Exploring the impact of the innovative compound 3-(3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-5-(pyridin-3-yl)-1H-pyrazol-1-yl) indolin-2-one on accelerating wound recovery.Scientific reports · 2026Article
- Identification of Novel Extracellular-Signal-Regulated Kinase 2 Inhibitors Through Machine Learning-Driven De Novo Design, Molecular Docking, and Free-Energy Perturbation.Pharmaceuticals (Basel, Switzerland) · 2026Article
- FGF 13 functions as a regulator of the ERK/aerobic glycolysis axis in the inflammatory state during septic lung injury.Nature communications · 2026Article
- Network pharmacology and molecular modelling analysis ofFrontiers in bioinformatics · 2026Article
- Integrating AI-Based Clustering, Molecular Dynamics, and Binding Energy Analysis to Elucidate Conformational Dynamics and Binding Selectivity in Extracellular Signal-Regulated Kinases 1 and 2 Complexes.Bioinformatics and biology insights · 2026Article
- Article
- Immunogenic cell death and tertiary lymphoid structures jointly define dysregulated antitumor immune states and therapeutic vulnerability in lung adenocarcinoma.Frontiers in immunology · 2026Article
- Molecular Frameworks for ERK1/2 Inhibition: Lessons from Synthetic and SAR Explorations.ACS omega · 2025Review
- Un-LOK-ing a New Approach for Conformational Selective Targeting of STK10 (LOK).ACS medicinal chemistry letters · 2025Article
- Progress of ERK Pathway-Modulated Natural Products for Anti-Non-Small-Cell Lung Cancer Activity.Pharmaceuticals (Basel, Switzerland) · 2025Review
68 more citing papers are in PubMed but not listed here.
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7 authors.
Funding
Abstract
Activation of the ERK pathway is a hallmark of cancer, and targeting of upstream signaling partners led to the development of approved drugs. Recently, SCH772984 has been shown to be a selective and potent ERK1/2 inhibitor. Here we report the structural mechanism for its remarkable selectivity. In ERK1/2, SCH772984 induces a so-far-unknown binding pocket that accommodates the piperazine-phenyl-pyrimidine decoration. This new binding pocket was created by an inactive conformation of the phosphate-binding loop and an outward tilt of helix αC. In contrast, structure determination of SCH772984 with the off-target haspin and JNK1 revealed two canonical but distinct type I binding modes. Notably, the new binding mode with ERK1/2 was associated with slow binding kinetics in vitro as well as in cell-based assay systems. The described binding mode of SCH772984 with ERK1/2 enables the design of a new type of specific kinase inhibitors with prolonged on-target activity.
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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.