PUBLICATION
Evaluation of Improved Glycogen Synthase Kinase-3α Inhibitors in Models of Acute Myeloid Leukemia
- Authors
- Neumann, T., Benajiba, L., Göring, S., Stegmaier, K., Schmidt, B.
- ID
- ZDB-PUB-151027-18
- Date
- 2015
- Source
- Journal of medicinal chemistry 58(22): 8907-19 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Cell Differentiation
- Cell Line, Tumor
- Enzyme Inhibitors/pharmacology*
- Enzyme Inhibitors/therapeutic use*
- Glycogen Synthase Kinase 3/antagonists & inhibitors*
- Glycogen Synthase Kinase 3/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
- PubMed
- 26496242 Full text @ J. Med. Chem.
Citation
Neumann, T., Benajiba, L., Göring, S., Stegmaier, K., Schmidt, B. (2015) Evaluation of Improved Glycogen Synthase Kinase-3α Inhibitors in Models of Acute Myeloid Leukemia. Journal of medicinal chemistry. 58(22):8907-19.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping