Oncotarget

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This article has been corrected. Correction in: Oncotarget. 2018; 9:20219.

Discovery of a FLT3 inhibitor LDD1937 as an anti-leukemic agent for acute myeloid leukemia

Hyo Jeong Lee, Jungeun Lee, Pyeonghwa Jeong, Jungil Choi, Juhwa Baek, Su Jin Ahn, Yeongyu Moon, Jeong Doo Heo, Young Hee Choi, Young-Won Chin, Yong-Chul Kim and Sun-Young Han _

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Oncotarget. 2018; 9:924-936. https://doi.org/10.18632/oncotarget.23221

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Abstract

Hyo Jeong Lee1,*, Jungeun Lee2,*, Pyeonghwa Jeong3,*, Jungil Choi4, Juhwa Baek1, Su Jin Ahn1, Yeongyu Moon5, Jeong Doo Heo5, Young Hee Choi5, Young-Won Chin5, Yong-Chul Kim2,3 and Sun-Young Han1

1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Republic of Korea

2School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea

3Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea

4Gyeongnam Department of Environment Toxicology and Chemistry, Korea Institutes of Toxicology, Jinju, Republic of Korea

5College of Pharmacy and BK21PLUS R-FIND Team, Dongguk University-Seoul, Goyang, Republic of Korea

*These authors contributed equally to the work

Correspondence to:

Sun-Young Han, email: [email protected]

Yong-Chul Kim, email: [email protected]

Keywords: FLT3; indirubin; acute myeloid leukemia; anti-tumor agent

Received: June 08, 2017     Accepted: November 03, 2017     Published: December 14, 2017

ABSTRACT

FMS-like receptor tyrosine kinase-3 (FLT3) belongs to the family of receptor tyrosine kinase (RTK), and the FLT3 mutation is observed in 1/3 of all acute myeloid leukemia (AML) patients. Potential FLT3 inhibitors have been investigated as potential therapeutic agents of AML. In this study, we identified a potent FLT3 inhibitor LDD1937 containing an indirubin skeleton. The potent inhibitory activity of LDD1937 against FLT3 was shown with an in vitro kinase assay (IC50 = 3 nM). The LDD1937 compound selectively inhibited the growth of MV-4-11 cells (GI50 = 1 nM) and induced apoptotic cell death. LDD1937 caused cell cycle arrest at the G2/M phase and increased the cell population at the sub-G1 phase. Phosphorylation of STAT5, which is the downstream signaling of FLT3, was significantly reduced by LDD1937 in a dose-dependent manner. The pharmacokinetic properties of LDD1937 were investigated in mice. Then, the in vivo anti-tumor effect was investigated using a MV-4-11 xenograft. With the intravenous administration of 5 and 10 mg/kg in nu/nu mice, the tumor volume and weight were significantly reduced compared to the control. LDD1937 is a promising therapeutic candidate to treat AML patients because of its ability to suppress tumor cell growth in vitro and in vivo.


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