Indirubin derivatives as potent FLT3 inhibitors with anti-proliferative activity of acute myeloid leukemic cells

Indirubin derivatives were identified as potent FLT3 tyrosine kinase inhibitors with anti-proliferative activity at acute myeloid leukemic cell lines, RS4; 11 and MV4; 11 which express FLT3-WT and FLT3-ITD mutation, respectively. Among several 5 and 5'-substituted indirubin derivatives, 5-fluoro analog, 13 exhibited potent inhibitory activity at FLT3 (IC50 = 15 nM) with more than 100-fold selectivity versus 6 other kinases and potent anti-proliferative effect for MV4; 11 cells (IC50 = 72 nM) with 30-fold selectivity versus RS4; 11 cells. Cell cycle analysis indicated that compound 13 induced cell cycle arrest at G(0)/G(1) phase in MV4; 11 cells. (C) 2010 Elsevier Ltd. All rights reserved.