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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, (22), 58. American Chemical Society, pp. 8907-8919, ISSN 0022-2623,
DOI: 10.25534/tuprints-00009652,
[Online-Edition: https://tuprints.ulb.tu-darmstadt.de/9652],
[Article]

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.

Item Type: Article
Erschienen: 2015
Creators: Neumann, Theresa and Benajiba, Lina and Göring, Stefan and Stegmaier, Kimberly and Schmidt, Boris
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
Divisions: 07 Department of Chemistry
07 Department of Chemistry > Organ Chemistry
Date Deposited: 08 Dec 2019 20:55
DOI: 10.25534/tuprints-00009652
Official URL: https://tuprints.ulb.tu-darmstadt.de/9652
URN: urn:nbn:de:tuda-tuprints-96525
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