ArticleACS chemical biology2013
Conformation-selective inhibitors reveal differences in the activation and phosphate-binding loops of the tyrosine kinases Abl and Src.
Article in ACS chemical biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 37 citations in OpenAlex.
- High-throughput screening and structure-guided design of small molecules enable modulation of SAL-PAP stress signaling.Journal of experimental botany · 2026Article
- The Discovery of Abl Kinase ATPase Activity and Its Implications in the Development of Straightforward Assays.ACS omega · 2025Article
- Structure and Dynamics of the ABL1 Tyrosine Kinase and Its Important Role in Chronic Myeloid Leukemia.Archiv der Pharmazie · 2025Review
- Ponatinib: A Review of the History of Medicinal Chemistry behind Its Development.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Profiling of drug resistance in Src kinase at scale uncovers a regulatory network coupling autoinhibition and catalytic domain dynamics.Cell chemical biology · 2024Article
- How many kinases are druggable? A review of our current understanding.The Biochemical journal · 2023Article
- Synthesis and Development of Highly Selective Pyrrolo[2,3-Journal of medicinal chemistry · 2023Article
- Overcoming phenotypic switching: targeting protein-protein interactions in cancer.Exploration of targeted anti-tumor therapy · 2023Review
- Structural Basis for Targeting the Folded P-Loop Conformation of c-MET.ACS medicinal chemistry letters · 2021Article
- A Chemical Probe for Dark Kinase STK17B Derives Its Potency and High Selectivity through a Unique P-Loop Conformation.Journal of medicinal chemistry · 2020Article
- Targeting Dynamic ATP-Binding Site Features Allows Discrimination between Highly Homologous Protein Kinases.ACS chemical biology · 2019Article
- What Makes a Kinase Promiscuous for Inhibitors?Cell chemical biology · 2019Article
- Survey of solution dynamics in Src kinase reveals allosteric cross talk between the ligand binding and regulatory sites.Nature communications · 2017Article
- Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations.Scientific reports · 2017Article
- Ponatinib promotes a G1 cell-cycle arrest of merlin/NF2-deficient human schwann cells.Oncotarget · 2017Article
- Structural and Functional Analysis of the Allosteric Inhibition of IRE1α with ATP-Competitive Ligands.ACS chemical biology · 2016Article
- Conformation-Selective Analogues of Dasatinib Reveal Insight into Kinase Inhibitor Binding and Selectivity.ACS chemical biology · 2016Article
- DARC: Mapping Surface Topography by Ray-Casting for Effective Virtual Screening at Protein Interaction Sites.Journal of medicinal chemistry · 2016Article
- Article
- A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics.Nature chemical biology · 2014Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Over the past decade, an increasingly diverse array of potent and selective inhibitors that target the ATP-binding sites of protein kinases have been developed. Many of these inhibitors, like the clinically approved drug imatinib (Gleevec), stabilize a specific catalytically inactive ATP-binding site conformation of their kinases targets. Imatinib is notable in that it is highly selective for its kinase target, Abl, over other closely related tyrosine kinases, such as Src. In addition, imatinib is highly sensitive to the phosphorylation state of Abl's activation loop, which is believed to be a general characteristic of all inhibitors that stabilize a similar inactive ATP-binding site conformation. In this report, we perform a systematic analysis of a diverse series of ATP-competitive inhibitors that stabilize a similar inactive ATP-binding site conformation as imatinib with the tyrosine kinases Src and Abl. In contrast to imatinib, many of these inhibitors have very similar potencies against Src and Abl. Furthermore, only a subset of this class of inhibitors is sensitive to the phosphorylation state of the activation loop of these kinases. In attempting to explain this observation, we have uncovered an unexpected correlation between Abl's activation loop and another flexible active site feature, called the phosphate-binding loop (p-loop). These studies shed light on how imatinib is able to obtain its high target selectivity and reveal how the conformational preference of flexible active site regions can vary between closely related kinases.
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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.