Development of phosphoinositide 3-kinase delta (PI3Kδ) inhibitors as potential anticancer agents through the generation of ligand-based pharmacophores and biological screening
PI3K delta signaling promotes cancer proliferation. To model this interesting target, we collected 79 PI3Kδ inhibitors of known bioactivities and divided them into four groups for pharmacophore modelling. Subsequent QSAR modelling ($ r^{2} $64 = 0.82, $ r^{2} $LOO = 0.86, F = 51.92, and $ r^{2} $PRESS versus 15 test inhibitors = 0.90) identified two optimal orthogonal pharmacophores that were evaluated using ROC curve analysis. The pharmacophores were subsequently used to mine the National Cancer Institute’s (NCI) chemical list for new anti-PI3Kδ hits. Subsequent in vitro evaluation identified ten hits of $ IC_{50} $ values ranging from 4.2–51.1 μM. Seven hits were found to be cytotoxic against A549 alveolar lung cancer cells. The most potent hit exhibited anti-PI3Kδ $ IC_{50} $ of 4.1 μM. Graphical Abstract Development of Phosphoinositide 3-kinase delta (PI3Kδ) Inhibitors as Potential Anticancer Agents Through the Generation of Ligand-Based Pharmacophores and Biological Screening..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:32 |
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| Enthalten in: |
Medicinal chemistry research - 32(2023), 6 vom: 18. Apr., Seite 1109-1121 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Al-Sha’er, Mahmoud A. [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| Themen: |
3D-QSAR |
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| Anmerkungen: |
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
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| doi: |
10.1007/s00044-023-03057-3 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a PI3K delta signaling promotes cancer proliferation. To model this interesting target, we collected 79 PI3Kδ inhibitors of known bioactivities and divided them into four groups for pharmacophore modelling. Subsequent QSAR modelling ($ r^{2} $64 = 0.82, $ r^{2} $LOO = 0.86, F = 51.92, and $ r^{2} $PRESS versus 15 test inhibitors = 0.90) identified two optimal orthogonal pharmacophores that were evaluated using ROC curve analysis. The pharmacophores were subsequently used to mine the National Cancer Institute’s (NCI) chemical list for new anti-PI3Kδ hits. Subsequent in vitro evaluation identified ten hits of $ IC_{50} $ values ranging from 4.2–51.1 μM. Seven hits were found to be cytotoxic against A549 alveolar lung cancer cells. The most potent hit exhibited anti-PI3Kδ $ IC_{50} $ of 4.1 μM. Graphical Abstract Development of Phosphoinositide 3-kinase delta (PI3Kδ) Inhibitors as Potential Anticancer Agents Through the Generation of Ligand-Based Pharmacophores and Biological Screening. | ||
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