Neumann, Theresa ; Benajiba, Lina ; Göring, Stefan ; Stegmaier, Kimberly ; Schmidt, Boris (2019)
Evaluation of Improved Glycogen Synthase Kinase-3α Inhibitors in Models of Acute Myeloid Leukemia.
doi: 10.25534/tuprints-00009652
Report, Erstveröffentlichung, Preprint
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Kurzbeschreibung (Abstract)
The challenge for glycogen synthase kinase-3 (GSK-3) inhibitor design lies in achieving high selectivity for one isoform over the other. The therapy of certain diseases, such as acute myeloid leukemia (AML), may require α-isoform specific targeting. The scorpion shaped GSK-3 inhibitors developed by our group achieved the highest GSK-3α selectivity reported so far but suffered from insufficient aqueous solubility. This work presents the solubility-driven optimization of our isoform-selective inhibitors using a scorpion shaped lead. Among 15 novel compounds, compound 27 showed high activity against GSK-3α/β with the highest GSK-3α selectivity reported to date. Compound 27 was profiled for bioavailability and toxicity in a zebrafish embryo phenotype assay. Selective GSK-3α targeting in AML cell lines was achieved with compound 27, resulting in a strong differentiation phenotype and colony formation impairment, confirming the potential of GSK-3α inhibition in AML therapy.
| Typ des Eintrags: | Report |
|---|---|
| Erschienen: | 2019 |
| Autor(en): | Neumann, Theresa ; Benajiba, Lina ; Göring, Stefan ; Stegmaier, Kimberly ; Schmidt, Boris |
| Art des Eintrags: | Erstveröffentlichung |
| Titel: | Evaluation of Improved Glycogen Synthase Kinase-3α Inhibitors in Models of Acute Myeloid Leukemia |
| Sprache: | Englisch |
| Publikationsjahr: | 6 Dezember 2019 |
| Ort: | Darmstadt |
| DOI: | 10.25534/tuprints-00009652 |
| URL / URN: | https://tuprints.ulb.tu-darmstadt.de/9652 |
| Zugehörige Links: | |
| Kurzbeschreibung (Abstract): | The challenge for glycogen synthase kinase-3 (GSK-3) inhibitor design lies in achieving high selectivity for one isoform over the other. The therapy of certain diseases, such as acute myeloid leukemia (AML), may require α-isoform specific targeting. The scorpion shaped GSK-3 inhibitors developed by our group achieved the highest GSK-3α selectivity reported so far but suffered from insufficient aqueous solubility. This work presents the solubility-driven optimization of our isoform-selective inhibitors using a scorpion shaped lead. Among 15 novel compounds, compound 27 showed high activity against GSK-3α/β with the highest GSK-3α selectivity reported to date. Compound 27 was profiled for bioavailability and toxicity in a zebrafish embryo phenotype assay. Selective GSK-3α targeting in AML cell lines was achieved with compound 27, resulting in a strong differentiation phenotype and colony formation impairment, confirming the potential of GSK-3α inhibition in AML therapy. |
| Status: | Preprint |
| URN: | urn:nbn:de:tuda-tuprints-96525 |
| Zusätzliche Informationen: | Ersch. auch in: Journal of Medicinal Chemistry, Vol 58/Issue 22, 2015 |
| Sachgruppe der Dewey Dezimalklassifikatin (DDC): | 500 Naturwissenschaften und Mathematik > 540 Chemie |
| Fachbereich(e)/-gebiet(e): | 07 Fachbereich Chemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Organische Chemie |
| Hinterlegungsdatum: | 20 Jun 2024 16:25 |
| Letzte Änderung: | 16 Okt 2024 09:57 |
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- Evaluation of Improved Glycogen Synthase Kinase-3α Inhibitors in Models of Acute Myeloid Leukemia. (deposited 20 Jun 2024 16:25) [Gegenwärtig angezeigt]
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