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Evaluation of Improved Glycogen Synthase Kinase-3α Inhibitors in Models of Acute Myeloid Leukemia

Neumann, Theresa ; Benajiba, Lina ; Göring, Stefan ; Stegmaier, Kimberly ; Schmidt, Boris (2015)
Evaluation of Improved Glycogen Synthase Kinase-3α Inhibitors in Models of Acute Myeloid Leukemia.
In: Journal of Medicinal Chemistry, 58 (22)
Artikel, Bibliographie

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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: Artikel
Erschienen: 2015
Autor(en): Neumann, Theresa ; Benajiba, Lina ; Göring, Stefan ; Stegmaier, Kimberly ; Schmidt, Boris
Art des Eintrags: Bibliographie
Titel: Evaluation of Improved Glycogen Synthase Kinase-3α Inhibitors in Models of Acute Myeloid Leukemia
Sprache: Englisch
Publikationsjahr: 2015
Ort: Darmstadt
Verlag: American Chemical Society
Titel der Zeitschrift, Zeitung oder Schriftenreihe: Journal of Medicinal Chemistry
Jahrgang/Volume einer Zeitschrift: 58
(Heft-)Nummer: 22
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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.

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: 02 Jul 2024 22:11
Letzte Änderung: 02 Jul 2024 22:11
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