Identification of 2-(4-pyridyl)thienopyridinones as GSK-3β inhibitors

Gentile, Gabriella; Bernasconi, Giovanni; Pozzan, Alfonso; Merlo, Giancarlo; Marzorati, Paola; Bamborough, Paul; Bax, Benjamin; Bridges, Angela; Brough, Caroline; Carter, Paul; Cutler, Geoffrey J.; Neu, Margarete; Takada, Mia

doi:10.1016/j.bmcl.2011.06.050

Cited by 24 publications

(17 citation statements)

References 11 publications

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“…Screening of the initial triazole library against a panel of kinases uncovered inhibitors of both GSK3β and FLT3. Another example of panel screening of fragment-like compounds reported was the discovery of thienopyridinone inhibitors of GSK3β [ 81 ]. Crystal structures obtained on the fi rst few fragments found and the information obtained from the binding mode regarding the molecular interactions were used to grow the molecule.…”

Section: Vbsmentioning

confidence: 99%

Fragment-Based Design of Kinase Inhibitors: A Practical Guide

Erickson

2015

Methods in Molecular Biology

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Fragment-based drug design has become an important strategy for drug design and development over the last decade. It has been used with particular success in the development of kinase inhibitors, which are one of the most widely explored classes of drug targets today. The application of fragment-based methods to discovering and optimizing kinase inhibitors can be a complicated and daunting task; however, a general process has emerged that has been highly fruitful. Here a practical outline of the fragment process used in kinase inhibitor design and development is laid out with specific examples. A guide to the overall process from initial discovery through fragment screening, including the difficulties in detection, to the computational methods available for use in optimization of the discovered fragments is reported.

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Section: Vbsmentioning

confidence: 99%

Fragment-Based Design of Kinase Inhibitors: A Practical Guide

Erickson

2015

Methods in Molecular Biology

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“…Recently, two new routes to 1 were described , including both Friedel–Crafts and reductive cyclization protocols. Even so, the classic “thermal” synthesis of Eloy and Deryckere continues to be applied for the preparation of benzopyridinones (and thienopyridinones) owing to procedural ease (for small scale) and inexpensive starting materials.…”

Section: Introductionmentioning

confidence: 66%

Thermal Synthesis of 3‐Bromothieno[3,2‐c]pyridin‐4‐(5H)‐one: A Telescoped Procedure with Tributylamine

Boros

Káldor

2014

Journal of Heterocyclic Chem

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3‐Bromothieno[3,2‐c]pyridine‐4‐(5H)‐one (1) was prepared from (2E)‐3‐(4‐bromo‐2‐thienyl)‐2‐propenoic acid (3) by the Eloy–Deryckere thermal benzo/heteropyridinone synthesis. A telescoped procedure was developed, which reduces some of the risk associated with the classic procedure. Use of tributylamine as an additive in this process was shown to facilitate E/Z‐isomerization of the intermediate vinyl isocyanate and lower the temperature necessary for the overall thermal process.

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“…The experimental ΔΔ G values were obtained by estimating the Δ G value of each compound first through the Cheng–Prusoff equation K i = IC50/(1 + S / K m ), where K i , S , and K m are the inhibition equilibrium constant, substrate (ATP) concentration, and Michaelis constant for the substrate (ATP), respectively. The IC50 value of the reference compound hptp is 126 n m , which was obtained from a previous study, and the associated S value is 10 μ m . In the present study, the S values for analogs 3 – 5 were all 25 μ m .…”

Section: Resultsmentioning

confidence: 99%

“…The investigated five analogs of hptp are referred to here as analogs 1 – 5 . The first two compounds were synthesized, and the affinity data are from a previous study by another group . The TI‐MD computations for the first two compounds with available crystal structures were intended for calibration purposes, and aptly reproduced the experimental relative binding free energy.…”

Section: Methodsmentioning

confidence: 99%

“…In the present study, we continued this effort and employed a first‐principles method, the thermodynamic integration (TI) method, to investigate the relative binding free energy of five compounds that are analogous to a reference compound with an available crystal structure. For all TI‐MD simulations, the compound 7‐(4‐hydroxyphenyl)‐2‐pyridin‐4‐yl‐5h‐thieno[3,2‐c]pyridin‐4‐one ( hptp ) in the GSK3β kinase‐inhibitor complexes with available crystal structures (pdb code: 3zrm) was selected as the reference compound (Figure ) . Docking computation was used for investigating binding modes of analogs 3 – 5 .…”

Section: Introductionmentioning

confidence: 99%

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Investigation of the bindings of a class of inhibitors with GSK3β kinase using thermodynamic integration MD simulation and kinase assay

Hsu

Lee

et al. 2017

Chem Biol Drug Des

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GSK3β kinase is a noteworthy target for discovery of the drugs that will be used to treat several diseases. In the effort to identify a new inhibitor lead compound, we utilized thermodynamic integration (TI)-molecular dynamics (MD) simulation and kinase assay to investigate the bindings between GSK3β kinase and five compounds that were analogous to a known inhibitor with an available crystal structure. TI-MD simulations of the first two compounds (analogs 1 and 2) were used for calibration. The computed binding affinities of analogs 1 and 2 agreed well with the experimental results. The rest three compounds (analogs 3-5) were newly obtained from a database search, and their affinity data were newly measured in our labs. TI-MD simulations predicted the binding modes and the computed ΔΔG values have a reasonably good correlation with the experimental affinity data. These newly identified inhibitors appear to be new leads according to our survey of GSK3β inhibitors listed in recent review articles. The predicted binding modes of these compounds should aid in designing new derivatives of these compounds in the future.

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Identification of 2-(4-pyridyl)thienopyridinones as GSK-3β inhibitors

Cited by 24 publications

References 11 publications

Fragment-Based Design of Kinase Inhibitors: A Practical Guide

Fragment-Based Design of Kinase Inhibitors: A Practical Guide

Thermal Synthesis of 3‐Bromothieno[3,2‐c]pyridin‐4‐(5H)‐one: A Telescoped Procedure with Tributylamine

Investigation of the bindings of a class of inhibitors with GSK3β kinase using thermodynamic integration MD simulation and kinase assay

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