RT Journal Article SR Electronic T1 Isoliquiritigenin, an orally available natural FLT3 inhibitor from licorice, exhibits selective anti-AML efficacy in vitro and in vivo JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.119.116129 DO 10.1124/mol.119.116129 A1 Zhi-Xing Cao A1 Yi Wen A1 Jun-Lin He A1 Shen-Zhen Huang A1 Fei Gao A1 Chuan-Jie Guo A1 Qing-Qing Liu A1 Shu-Wen Zheng A1 Dao-Yin Gong A1 Yu-Zhi Li A1 Ruo-Qi Zhang A1 Jian-Ping Chen A1 Cheng Peng YR 2019 UL http://molpharm.aspetjournals.org/content/early/2019/08/28/mol.119.116129.abstract AB Licorice is a medicinal herb widely used to treat inflammation-related diseases in china. Isoliquiritigenin (ISL) is an important constituent of Licorice, and possesses multiple bioactivitys. In this study, we examined the selective anti-AML (Acute myeloid leukemia) property of ISL via targeting FLT3, a certified valid target for the treatment of AML. In vitro, ISL potently inhibited FLT3 kinase with an IC50 of 115.1 ± 4.2 nM, selectively inhibited the viability of FLT3-ITD or FLT3-ITD/F691L mutant AML cells, and showed very weak activity towards other tested cell lines or kinases.Western blotting detection revealed that ISL potently inhibited the activation of FLT3/Erk1/2/STAT5 signal in AML cells. Meanwhile, Molecular docking study indicated that ISL could stably form aromatic interactions and hydrogen bonds within the kinase domain of FLT3. In vivo, oral administration of ISL significantly inhibited the MV4-11 tumor growth and prolonged the survival time of bone marrow engraftment AML mice via decreasing the expression of Ki67, and induced apoptosis. Taken together, the present study identified a novel function of ISL as a selective FLT3 inhibitor to be a promising novel potential natural bioactive compound for the treatment of AML with FLT3-ITD or FLT3-ITD/F691L mutations. Thus, ISL and licorice might posess potential therapeutic effects in the treatment of AML, and combining with other drugs maight provide more effective treatment strategy.SIGNIFICANCE STATEMENT Isoliquiritigenin selectively inhibited the viability of FLT3-ITD mutant AML cells via targeting FLT3 Oral administration of Isoliquiritigenin could significantly inhibit in vivo tumor growth of AML cells in xenograft tumor model and bone marrow model with well tolerance. Isoliquiritigenin is an orally available natural FLT3 inhibitor from licorice. Isoliquiritigenin still retained a good inhibitory activity against FLT3-ITD/F691L mutation, a resistance kinase domain mutation against sorafenib and AC220