Proteolysis-Targeting\nChimera (PROTAC) Modification\nof Dovitinib Enhances the Antiproliferative Effect against FLT3-ITD-Positive\nAcute Myeloid Leukemia Cells

Abstract

Acute\nmyeloid leukemia (AML) refers to one of the most lethal blood\nmalignancies worldwide. FLT3-ITD mutation is recognized as the most\ncommon one that predicted a poorer prognosis. There have been many\nprominent FLT3-ITD inhibitors approved by the FDA for clinical therapies.\nHowever, as impacted by undesirable off-target effects, differentiated\nmetabolic issues, and clinical drug resistance problems, it remains\nchallenging to discover alternative and promising solutions for treating\nFLT3-ITD⁺ AML. In this study, dovitinib was chemically\nmodified and converted into CRBN-recruiting PROTACs. Two active compounds\nwere identified, which showed enhanced antiproliferative effects against\nFLT3-ITD⁺ AML cells, both <i>in vitro</i> and <i>in vivo</i>. As demonstrated from further biological evaluation,\nthe compounds could induce the degradation of the FLT3-ITD and KIT\nproteins in a ubiquitin–proteasome-dependent manner and completely\nblock their downstream signaling pathway. The findings of this study\nwould provide another promising strategy to develop novel therapies\nfor FLT3-ITD⁺ AML.