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Example:10.1021/acsami.1c06204 or Chem. Rev., 2007, 107, 2411-2502
Proteolysis-Targeting Chimera (PROTAC) Modification of Dovitinib Enhances the Antiproliferative Effect against FLT3-ITD-Positive Acute Myeloid Leukemia Cells
Journal of Medicinal Chemistry  (IF7.446),  Pub Date : 2021-10-25, DOI: 10.1021/acs.jmedchem.1c00996
Sheng Cao, Lan Ma, Yulin Liu, Mingming Wei, Yuhong Yao, Chen Li, Ruonan Wang, Ning Liu, Zhiqiang Dong, Xuechun Li, Ming Li, Xiaoji Wang, Cheng Yang, Guang Yang

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.