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), pp. 8907-8919. American Chemical Society, ISSN 0022-2623,
DOI: 10.25534/tuprints-00009652,
[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 ; Benajiba, Lina ; Göring, Stefan ; Stegmaier, Kimberly ; 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 |
| Volume of the journal: | 58 |
| Issue 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 |
| URL / URN: | https://tuprints.ulb.tu-darmstadt.de/9652 |
| URN: | urn:nbn:de:tuda-tuprints-96525 |
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| Corresponding Links: | |
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