ArticleFrontiers in molecular biosciences2020
Structure and Characterization of a Covalent Inhibitor of Src Kinase.
Article in Frontiers in molecular biosciences, 2020. 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, 27 citations in OpenAlex.
- Subtimizer: Computational Workflow for Structure-Guided Design of Potent and Selective Kinase Peptide Substrates.Journal of chemical information and modeling · 2026Article
- SRC kinase drives multidrug resistance induced by KRAS-G12C inhibition.Science advances · 2024Article
- Network Pharmacology and Molecular Docking Reveal Anti-Asthmatic Potential ofPharmaceuticals (Basel, Switzerland) · 2024Article
- Bioinformatics and computational studies of chabamide F and chabamide G for breast cancer and their probable mechanisms of action.Scientific reports · 2024Article
- Selective and Potent PROTAC Degraders of c-Src Kinase.ACS chemical biology · 2024Article
- LIMS-Kinase provides sensitive and generalizable label-freeCell reports. Physical science · 2023Article
- Targeting Breast Cancer: The Familiar, the Emerging, and the Uncharted Territories.Biomolecules · 2023Review
- Elucidation of Pharmacological Mechanism Underlying the Anti-Alzheimer's Disease Effects ofMolecules (Basel, Switzerland) · 2023Article
- A back-door insight into the modulation of Src kinase activity by the polyamine spermidine.eLife · 2023Article
- Synthesis and biological activity evaluation of 3-(hetero) arylideneindolin-2-ones as potential c-Src inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2022Article
- Validation of an Allosteric Binding Site of Src Kinase Identified by Unbiased Ligand Binding Simulations.Journal of molecular biology · 2022Article
- Network pharmacology and experimental verification based research into the effect and mechanism of Aucklandiae Radix-Amomi Fructus against gastric cancer.Scientific reports · 2022Article
- Covalent Proximity Scanning of a Distal Cysteine to Target PI3Kα.Journal of the American Chemical Society · 2022Article
- Combining Network Pharmacology with Molecular Docking for Mechanistic Research on Thyroid Dysfunction Caused by Polybrominated Diphenyl Ethers and Their Metabolites.BioMed research international · 2021Article
- Unveiling the Anticancer Potential and Molecular Mechanisms of Fangchinoline Against Cholangiocarcinoma Using FTIR Microspectroscopy, In Vitro and In Silico Approaches.Integrative cancer therapiesArticle
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Unregulated Src activity promotes malignant processes in cancer, but no Src-directed targeted therapies are used clinically, possibly because early Src inhibitors produce off-target effects leading to toxicity. Improved selective Src inhibitors may enable Src-directed therapies. Previously, we reported an irreversible Src inhibitor, DGY-06-116, based on the hybridization of dasatinib and a promiscuous covalent kinase probe SM1-71. Here, we report biochemical and biophysical characterization of this compound. An x-ray co-crystal structure of DGY-06-116: Src shows a covalent interaction with the kinase p-loop and occupancy of the back hydrophobic kinase pocket, explaining its high potency, and selectivity. However, a reversible analog also shows similar potency. Kinetic analysis shows a slow inactivation rate compared to other clinically approved covalent kinase inhibitors, consistent with a need for p-loop movement prior to covalent bond formation. Overall, these results suggest that a strong reversible interaction is required to allow sufficient time for the covalent reaction to occur. Further optimization of the covalent linker may improve the kinetics of covalent bond formation.
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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.