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

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.

• Authors: Theresa Neumann, Lina Benajiba, Stefan Göring, Kimberly Stegmaier, Boris Schmidt
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 22 Pg. 8907-19 (Nov 25 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 26496242 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Isoenzymes
• Glycogen Synthase Kinase 3 beta
• Glycogen Synthase Kinase 3
• glycogen synthase kinase 3 alpha

Topics

• Animals
• Cell Differentiation
• Cell Line, Tumor
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, chemistry)
• Glycogen Synthase Kinase 3 beta
• HL-60 Cells
• Humans
• Isoenzymes
• Leukemia, Myeloid, Acute (drug therapy)
• Models, Molecular
• Molecular Conformation
• Solubility
• Structure-Activity Relationship
• Tumor Stem Cell Assay
• Zebrafish