Proteolysis-Targeting Chimera (PROTAC) Modification of Dovitinib Enhances the Antiproliferative Effect against FLT3-ITD-Positive Acute Myeloid Leukemia Cells

Acute
myeloid leukemia (AML) refers to one of the most lethal blood
malignancies worldwide. FLT3-ITD mutation is recognized as the most
common one that predicted a poorer prognosis. There have been many
prominent FLT3-ITD inhibitors approved by the FDA for clinical therapies.
However, as impacted by undesirable off-target effects, differentiated
metabolic issues, and clinical drug resistance problems, it remains
challenging to discover alternative and promising solutions for treating
FLT3-ITD+ AML. In this study, dovitinib was chemically
modified and converted into CRBN-recruiting PROTACs. Two active compounds
were identified, which showed enhanced antiproliferative effects against
FLT3-ITD+ AML cells, both in vitro and in vivo. As demonstrated from further biological evaluation,
the compounds could induce the degradation of the FLT3-ITD and KIT
proteins in a ubiquitin–proteasome-dependent manner and completely
block their downstream signaling pathway. The findings of this study
would provide another promising strategy to develop novel therapies
for FLT3-ITD+ AML.