SU11652 Inhibits tyrosine kinase activity of FLT3 and growth of MV-4-11 cells

Journal of Hematology & Oncology

Zhizhuang Joe Zhao²  Xueqi Fu³  Xuesong Xu¹  Yun Chen²  Yao Guo² 

[1] Clinical Laboratory, China Japan Union Hospital, Jilin University, Changchun, China;Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, 73104, USA;Edmond H. Fischer Signal Transduction Laboratory, College of Life Sciences, Jilin University, Changchun, China

关键词: Acute myeloid leukemia;    SU11652;    Inhibitor screening;    FLT3;    Tyrosine kinase;   

Others  :  812692
DOI  :  10.1186/1756-8722-5-72

 received in 2012-10-24, accepted in 2012-11-26,  发布年份 2012

【 摘 要 】

Background

FLT3-ITD and FLT3-TKD mutations are frequently found in acute myeloid leukemia (AML). This makes tyrosine kinase FLT3 a highly attractive target for therapeutic drug development. However, effective drugs have not yet emerged. This study is intended to identify and to characterize new FLT3 inhibitors.

Methods

By using the protein substrate GST-FLT3S to analyze kinase activity of recombinant proteins carrying the catalytic domain of wild type and mutant forms of FLT3, we screened a chemical library containing 80 known protein kinase inhibitors. We identified SU11652 as a potent FLT3 inhibitor and further employed FLT3-ITD-positive MV- 4–11 cells to study its effects on cell growth, apoptosis, cell cycles, and cell signaling.

Results

SU11652 strongly inhibited the activity of wild type, D835Y, and D835H mutant forms of FLT3 with IC₅₀ values of 1.5, 16, and 32 nM, respectively. It effectively blocked the growth of FLT3-ITD -positive MV-4-11 cells at nanomolar concentrations but exhibited much less effects on several other cells which do not carry mutations of FLT3. SU11652 inhibited growth of MV-4-11 cells by inducing apoptosis, causing cell cycle arrest, and blocking activation of the ERK, Akt, and STAT signaling pathways.

Conclusion

SU11652 is a potent FLT3 inhibitor which selectively targets FLT3-ITD-positive cells. It should serve as a good candidate for development of therapeutic drugs to treat AML.

【 授权许可】

   
2012 Guo et al.; licensee BioMed Central Ltd.

【 图 表 】

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