ArticleThe Journal of biological chemistry2011
Structural basis for selective small molecule kinase inhibition of activated c-Met.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 38 citations in OpenAlex.
- Medicinal Chemistry of Small-Molecule c-Met Inhibitors: From Approved Therapies to Emerging Multitarget Anticancer Agents.International journal of molecular sciences · 2026Review
- Autoregulation of the MET receptor tyrosine kinase by its intracellular juxtamembrane domain.The Biochemical journal · 2025Article
- Cross-activating c-Met/β1 integrin complex drives metastasis and invasive resistance in cancer.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- The Axl kinase domain in complex with a macrocyclic inhibitor offers first structural insights into an active TAM receptor kinase.The Journal of biological chemistry · 2017Article
- Structural Basis of TPR-Mediated Oligomerization and Activation of Oncogenic Fusion Kinases.Structure (London, England : 1993) · 2017Article
- Pharmacophore Mapping Approach for Drug Target Identification: A Chemical Synthesis and in Silico Study on Novel Thiadiazole Compounds.Journal of clinical and diagnostic research : JCDR · 2017Article
- PKG II reverses HGF-triggered cellular activities by phosphorylating serine 985 of c-Met in gastric cancer cells.Oncotarget · 2016Article
- An engineered dimeric fragment of hepatocyte growth factor is a potent c-MET agonist.FEBS letters · 2014Article
- Autoinhibition of the Ron receptor tyrosine kinase by the juxtamembrane domain.Cell communication and signaling : CCS · 2014Article
- Article
- Fragment-based strategy for structural optimization in combination with 3D-QSAR.Journal of computer-aided molecular design · 2013Article
- Anthraquinone Derivatives as Potent Inhibitors of c-Met Kinase and the Extracellular Signaling Pathway.ACS medicinal chemistry letters · 2013Article
- Targeting MET in cancer: rationale and progress.Nature reviews. Cancer · 2012Review
Corrections and comments
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Authors and funding
18 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The receptor tyrosine kinase c-Met is implicated in oncogenesis and is the target for several small molecule and biologic agents in clinical trials for the treatment of cancer. Binding of the hepatocyte growth factor to the cell surface receptor of c-Met induces activation via autophosphorylation of the kinase domain. Here we describe the structural basis of c-Met activation upon autophosphorylation and the selective small molecule inhibiton of autophosphorylated c-Met. MK-2461 is a potent c-Met inhibitor that is selective for the phosphorylated state of the enzyme. Compound 1 is an MK-2461 analog with a 20-fold enthalpy-driven preference for the autophosphorylated over unphosphorylated c-Met kinase domain. The crystal structure of the unbound kinase domain phosphorylated at Tyr-1234 and Tyr-1235 shows that activation loop phosphorylation leads to the ejection and disorder of the activation loop and rearrangement of helix αC and the G loop to generate a viable active site. Helix αC adopts a orientation different from that seen in activation loop mutants. The crystal structure of the complex formed by the autophosphorylated c-Met kinase domain and compound 1 reveals a significant induced fit conformational change of the G loop and ordering of the activation loop, explaining the selectivity of compound 1 for the autophosphorylated state. The results highlight the role of structural plasticity within the kinase domain in imparting the specificity of ligand binding and provide the framework for structure-guided design of activated c-Met inhibitors.
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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.