Discovery of 3-amide-pyrimidine-based derivatives as potential fms-like tyrosine receptor kinase 3 (FLT3) inhibitors for treating acute myelogenous leukemia

Bioorg Med Chem Lett. 2024 Dec 19:130082. doi: 10.1016/j.bmcl.2024.130082. Online ahead of print.

Abstract

FLT3-ITD and TKD mutants play a central role in acute myeloid leukemia (AML), making FLT3 an attractive target for AML treatment. To discover next-generation FLT3 inhibitors and gather additional structure-activity relationship (SAR) information, we performed structural modifications of G-749 (denfivontinib) utilizing structure simplification and scaffold hopping strategies. Among these derivatives, MY-10 exhibited the most potent and selective inhibition of MV4-11 cell proliferation, demonstrating potent inhibitory activity against FLT3-ITD (IC50 = 6.5 nM) and FLT3-D835Y (IC50 = 10.3 nM) mutants. Notably, MY-10 exhibited no inhibitory activity against c-KIT kinase (IC50 > 100 μM). Mechanistic studies revealed that MY-10 arrested the cell cycle at the G0/G1 phase and efficiently induced apoptosis. Furthermore, it significantly reduced reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP), and strongly inhibited FLT3-mediated signaling pathways. These findings, along with the obtained SAR information, provide valuable insights for the further development of FLT3 inhibitors.

Keywords: Acute myelogenous leukemia; Antitumor activity; FLT3 inhibitor; Structural optimization.