HM43239 is an orally active and selective FLT3 inhibitor with IC50s of 1.1 nM, 1.8 nM and 1.0 nM for FLT3 WT, FLT3 internal tandem duplication (ITD) and FLT3 D835Y kinases, respectively. HM43239 inhibits the kinase activity of FLT3 as a reversible type I inhibitor and modulates p-STAT5, p-ERK, SYK, JAK1/2, and TAK1. HM43239 inhibits the proliferation and induces the apoptosis of leukemic cells[2].IC50 & Target:IC50: 1.1 nM (FLT3 WT), 1.8 nM (FLT3 ITD) and 1.0 nM (FLT3 D835Y)In Vitro: HM43239 potently inhibits the growth of acute myeloid leukemia cell lines harboring FLT3 ITD mutation, such as MV4-11 (IC50: 1.3 nM), MOLM-13 (IC50: 5.1 nM), and MOLM-14 (IC50: 2.9 nM). HM43239 also inhibits KG1a cells (CD34+/CD38- cells) proliferation.
HM43239 induces the caspase 3/7-dependent apoptosis of leukemic stem cell (LSC) marker-expressing KG1a cells (CD34+/CD38- cells).
HM43239 potently inhibits phosphorylation of SYK, STAT3, and STAT5 in KG1a cells.In Vivo: HM43239 shows the excellent dose proportional antitumor activity in mouse models xenografted with both MV4-11 and MOLM-13 cell lines without any significant toxicity.
HM43239 prolongs survival in FLT3 ITD/TKD double mutated xenograft mouse models.