FLT3 Inhibitor HM43239: Targeting Acute Myeloid Leukemia with High Potency and Selectivity

Acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) mutations is linked to an unfavorable prognosis, high relapse risk, and lower overall survival rates. FLT3 inhibitors have shown clinical benefits for AML patients with these mutations. HM43239 is a newly characterized FLT3 inhibitor with high potency and selectivity, which was assessed for its therapeutic potential in AML.

HM43239 demonstrated tight binding to FLT3 kinase and high selectivity for FLT3 and other AML-associated kinases such as SYK, JAK, and TAK1. It showed low IC50 values against FLT3 wild type, FLT3 ITD, and FLT3 D835Y kinases. HM43239 effectively inhibited the growth of AML cell lines with FLT3 ITD mutations and reduced the phosphorylation levels of FLT3 and downstream kinases involved in cell proliferation. It also induced apoptosis in AML cell lines expressing the FLT3 ITD mutation and affected leukemic stem cells (LSC), suggesting the potential to target LSC.

In mouse models xenografted with MV4-11 and MOLM-13 cell lines, HM43239 exhibited dose-proportional antitumor activity without significant toxicity. The compound also modulated in vivo targets related to AML with FLT3 mutations, such as p-FLT3 and p-STAT5.

In conclusion, HM43239 has shown promise as a potential therapeutic agent for the treatment of AML, with mechanisms that may help overcome resistance and prevent relapse in patients with FLT3-mutated AML.