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

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• 作者：Theresa Neumann ; Lina Benajiba ; Stefan G枚ring ; Kimberly Stegmaier ; Boris Schmidt
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：November 25, 2015
• 年：2015
• 卷：58
• 期：22
• 页码：8907-8919
• 全文大小：647K
• ISSN：1520-4804

文摘

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 伪-isoform specific targeting. The scorpion shaped GSK-3 inhibitors developed by our group achieved the highest GSK-3伪 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-3伪/尾 with the highest GSK-3伪 selectivity reported to date. Compound 27 was profiled for bioavailability and toxicity in a zebrafish embryo phenotype assay. Selective GSK-3伪 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-3伪 inhibition in AML therapy.