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

Neumann, Theresa and Benajiba, Lina and Göring, Stefan and Stegmaier, Kimberly and Schmidt, Boris (2015):
Evaluation of Improved Glycogen Synthase Kinase-3α Inhibitors in Models of Acute Myeloid Leukemia.
In: Journal of Medicinal Chemistry, 58, (22), American Chemical Society, ISSN 0022-2623,
DOI: 10.25534/tuprints-00009652,
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Item Type: Article
Title: Evaluation of Improved Glycogen Synthase Kinase-3α Inhibitors in Models of Acute Myeloid Leukemia
Language: English
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.

Journal or Publication Title: Journal of Medicinal Chemistry
Journal volume: 58
Number: 22
Publisher: American Chemical Society
Classification DDC: 500 Naturwissenschaften und Mathematik > 540 Chemie
Divisions: 07 Department of Chemistry > Organ Chemistry
Date Deposited: 06 Dec 2019 07:43
Last Modified: 10 Dec 2019 14:03
DOI: 10.25534/tuprints-00009652
Related URLs:
URN: urn:nbn:de:tuda-tuprints-96525
URI: https://tuprints.ulb.tu-darmstadt.de/id/eprint/9652
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