ArticleThe Journal of biological chemistry2017
The Axl kinase domain in complex with a macrocyclic inhibitor offers first structural insights into an active TAM receptor kinase.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 61 citations in OpenAlex.
- From cabozantinib to zanzalintinib: obvious chemical modifications as a new frontier in product hopping.Nature biotechnology · 2026Article
- Discovery of potential AXL inhibitors using virtual screening, molecular docking, molecular dynamics, molecular mechanics, and in vitro validation.Scientific reports · 2026Article
- Structure-Based Drug Discovery of Triazine Derivatives as Potent and Orally Bioavailable AXL Inhibitors for Cancer Therapy.ACS omega · 2026Article
- Structural Analysis of Tilvestamab in Complex with AXL.ACS omega · 2026Article
- Aberrant activation of AXL may drive progression of squamous cell carcinoma in CLL patients: a mechanistic study with clinical implications.British journal of cancer · 2024Article
- Discovery of Dual MER/AXL Kinase Inhibitors as Bifunctional Small Molecules for Inhibiting Tumor Growth and Enhancing Tumor Immune Microenvironment.Journal of medicinal chemistry · 2024Article
- Conserved regulatory motifs in the juxtamembrane domain and kinase N-lobe revealed through deep mutational scanning of the MET receptor tyrosine kinase domain.bioRxiv : the preprint server for biology · 2024Article
- An Intriguing Purview on the Design of Macrocyclic Inhibitors for Unexplored Protein Kinases through Their Binding Site Comparison.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Structure-based discovery of potent inhibitors of Axl: design, synthesis, and biological evaluation.RSC medicinal chemistry · 2022Article
- Article
- Synthesis and Characterization of a Click-Assembled 18-Atom Macrocycle That Displays Selective AXL Kinase Inhibitory Activity.ACS omega · 2019Article
- Rational Drug Design of Axl Tyrosine Kinase Type I Inhibitors as Promising Candidates Against Cancer.Frontiers in chemistry · 2019Article
- Chronic lymphocytic leukemia cells from ibrutinib treated patients are sensitive to Axl receptor tyrosine kinase inhibitor therapy.Oncotarget · 2018Article
- HGF-induced formation of the MET-AXL-ELMO2-DOCK180 complex promotes RAC1 activation, receptor clustering, and cancer cell migration and invasion.The Journal of biological chemistry · 2018Article
- Development of Potent Inhibitors of Receptor Tyrosine Kinases by Ligand-Based Drug Design and Target-Biased Phenotypic Screening.Journal of medicinal chemistry · 2018Article
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The receptor tyrosine kinase family consisting of Tyro3, Axl, and Mer (TAM) is one of the most recently identified receptor tyrosine kinase families. TAM receptors are up-regulated postnatally and maintained at high levels in adults. They all play an important role in immunity, but Axl has also been implicated in cancer and therefore is a target in the discovery and development of novel therapeutics. However, of the three members of the TAM family, the Axl kinase domain is the only one that has so far eluded structure determination. To this end, using differential scanning fluorimetry and hydrogen-deuterium exchange mass spectrometry, we show here that a lower stability and greater dynamic nature of the Axl kinase domain may account for its poor crystallizability. We present the first structural characterization of the Axl kinase domain in complex with a small-molecule macrocyclic inhibitor. The Axl crystal structure revealed two distinct conformational states of the enzyme, providing a first glimpse of what an active TAM receptor kinase may look like and suggesting a potential role for the juxtamembrane region in enzyme activity. We noted that the ATP/inhibitor-binding sites of the TAM members closely resemble each other, posing a challenge for the design of a selective inhibitor. We propose that the differences in the conformational dynamics among the TAM family members could potentially be exploited to achieve inhibitor selectivity for targeted receptors.
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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.