Development and bio-evaluation of novel indolizine derivatives in FLT3 mutant acute myeloid leukemia cells

Acute myeloid leukemia (AML) is a highly malignant blood tumor, and FLT3 serves as an important molecular target for the treatment of AML. Currently, FLT3 inhibitors still have issues of drug resistance and unsatisfactory clinical efficacy in the treatment of AML. Indolizine derivatives exhibit good antibacterial and antitumor biological activities. Based on the synthesis and identification of a library of multiple indolizine lead compounds and screening of their antitumor activities, we evaluated a novel indolizine derivative, 8h, which exhibited more sensitivity in inhibiting FLT3-mutated AML cells MV4-11 and MOLM13. 8h concentration-dependently induced apoptosis of MV4-11 cells, as well as cell cycle arrest and mitochondrial membrane potential reduction. Treatment with 8h downregulated the expression levels of FLT3 protein and downstream signaling proteins, and induced the activation of apoptosis-related proteins Caspase-3 and Caspase-9. The novel indolizine derivative 8h has a good inhibitory effect on FLT3-mutated AML cells and has the potential to become a FLT3 inhibitor.