PUBLICATION
SKLB-677, an FLT3 and Wnt/β-catenin signaling inhibitor, displays potent activity in models of FLT3-driven AML
- Authors
- Ma, S., Yang, L.L., Niu, T., Cheng, C., Zhong, L., Zheng, M.W., Xiong, Y., Li, L.L., Xiang, R., Chen, L.J., Zhou, Q., Wei, Y.Q., Yang, S.Y.
- ID
- ZDB-PUB-170214-90
- Date
- 2015
- Source
- Scientific Reports 5: 15646 (Journal)
- Registered Authors
- Keywords
- Acute myeloid leukaemia, Targeted therapies
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Antineoplastic Agents/pharmacology*
- Apoptosis/drug effects
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Cell Survival/drug effects
- Drug Resistance, Neoplasm
- Female
- G1 Phase Cell Cycle Checkpoints/drug effects
- Humans
- Isoxazoles/pharmacology*
- Leukemia, Myeloid, Acute/drug therapy*
- Mice
- Mice, Inbred NOD
- Mice, SCID
- Phenylurea Compounds/chemistry
- Pyrazoles/chemistry
- Pyrimidines/chemistry
- Urea/analogs & derivatives*
- Urea/pharmacology
- Wnt Proteins/antagonists & inhibitors*
- Wnt Signaling Pathway/drug effects*
- Zebrafish
- beta Catenin/antagonists & inhibitors*
- fms-Like Tyrosine Kinase 3/antagonists & inhibitors*
- PubMed
- 26497577 Full text @ Sci. Rep.
Citation
Ma, S., Yang, L.L., Niu, T., Cheng, C., Zhong, L., Zheng, M.W., Xiong, Y., Li, L.L., Xiang, R., Chen, L.J., Zhou, Q., Wei, Y.Q., Yang, S.Y. (2015) SKLB-677, an FLT3 and Wnt/β-catenin signaling inhibitor, displays potent activity in models of FLT3-driven AML. Scientific Reports. 5:15646.
Abstract
FLT3 has been identified as a valid target for the treatment of acute myeloid leukemia (AML), and some FLT3 inhibitors have shown very good efficacy in treating AML in clinical trials. Nevertheless, recent studies indicated that relapse and drug resistance are still difficult to avoid, and leukemia stem cells (LSCs) are considered one of the most important contributors. Here, we report the characterization of SKLB-677, a new FLT3 inhibitor developed by us recently. SKLB-677 exhibits low nanomolar potency in biochemical and cellular assays. It is efficacious in animal models at doses as low as 1mg/kg when administrated orally once daily. In particular, SKLB-677 but not first-generation and second-generation FLT3 inhibitors in clinical trials has the ability to inhibit Wnt/β-catenin signaling; Wnt/β-catenin signaling is required for the development of LSCs, but not necessary for the development of adult hematopoietic stem cells (HSCs). This compound indeed showed considerable suppression effects on leukemia stem-like cells in in vitro functional assays, but had no influence on normal HSCs. Collectively, SKLB-677 is an interesting lead compound for the treatment of AML, and deserves further investigations.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping