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

// Hyo Jeong Lee 1, * , Jungeun Lee 2, * , Pyeonghwa Jeong 3, * , Jungil Choi 4 , Juhwa Baek 1 , Su Jin Ahn 1 , Yeongyu Moon 5 , Jeong Doo Heo 5 , Young Hee Choi 5 , Young-Won Chin 5 , Yong-Chul Kim 2, 3 and Sun-Young Han 1 1 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Republic of Korea 2 School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea 3 Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea 4 Gyeongnam Department of Environment Toxicology and Chemistry, Korea Institutes of Toxicology, Jinju, Republic of Korea 5 College 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: syhan@gnu.ac.kr Yong-Chul Kim, email: yongchul@gist.ac.kr 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 (IC 50 = 3 nM). The LDD1937 compound selectively inhibited the growth of MV-4-11 cells (GI 50 = 1 nM) and induced apoptotic cell death. LDD1937 caused cell cycle arrest at the G 2 /M phase and increased the cell population at the sub-G 1 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 .