Danatinib is a potent and selective FLT3 inhibitor with IC50 of 3 nM, overcomes acquired resistance and shows effective inhibition against FLT3-ITD and/or FLT3-TKD mutations.
Danatinib exhibits excellent selectivity profile on 310 kinases with an S score (1) of 0.058, with exception kinases RET and KIT (IC50<10 nM).
Danatinib displays antiproliferative activities by targeting FLT3-ITD and/or secondary mutations, which include FLT3-ITD-N676D, FLT3-ITD-F691L, FLT3-ITD-G697R, FLT3-ITD-D835V, FLT3-ITD-D835Y and FLT3-ITD-Y842H (IC50=0.9-818 nM).
Danatinib has stronger antiproliferative effects compared to linifanib in both MV4-11 and MOLM-13 cells with IC50 of 4.6 nM and 0.89  nM, respectively.
Danatinib effectively induces G0-G1 cell cycle arrest in both MV4-11 and MOLM-13 cells and triggers cell death via inhibition of FLT3-mediated signaling.
Danatinib dose-dependently blocks the phosphorylation of FLT3 and completely suppresses FLT3 autophosphorylation at 100  nM in MV4–11 cells.
Danatinib dose-dependently inhibits the phosphorylation of FLT3 and its downstream signaling pathway mediators STAT5, AKT and ERK, decreasse the cellular ROS level in FLT3-ITD AML cells.
Danatinib (10 -50 mg/kg, once a day, i.p.) exhibit excellent antitumor efficacy in AML MV4–11 xenograft model, without myelosuppressive toxicity.