Abstract
Target protein degrader is a new paradigm in the small molecule drug discovery field and relates to the term ‘event-driven pharmacology’. Fms-like tyrosine kinase 3 (FLT3) is a significant target for treating acute myeloid leukemia (AML). A few FLT3 kinase inhibitors are currently used in the clinic for AML patients. However, resistance to current FLT3 inhibitors has emerged, and strategies to overcome this resistance are required. Small molecules downregulating FLT3 protein level are reported, exhibiting antileukemic effects against AML cell lines. Small molecules with various mechanisms such as Hsp90 inhibition, proteasome inhibition, RET inhibition, and USP10 inhibition are explained. In addition, reports of FLT3 as a client of Hsp90, current knowledge of the ubiquitin proteasome system for FLT3 degradation, the relationship with FLT3 phosphorylation status and susceptibility of FLT3 degradation are discussed.
Highlights
Pharmaceuticals 2022, 15, 320 the major targets for acute myeloid leukemia (AML) therapy, and activating mutations of Fms-like tyrosine kinase 3 (FLT3) are found in approximately one-third of AML and less than 3% of acute lymphoblastic leukemia patients [6,7]
While most investigations have concentrated on the kinase activity inhibition of FLT3 for AML therapeutics, several small molecules downregulating the FLT3 protein expression have been reported
Interaction between FLT-wt and Hsp90, was not observed. These results suggest that only FLT3-ITD, not FLT-wt, is the client of Hsp90 protein
Summary
Pharmaceuticals 2022, 15, 320 the major targets for AML therapy, and activating mutations of FLT3 are found in approximately one-third of AML and less than 3% of acute lymphoblastic leukemia patients [6,7]. Small molecules inhibiting the kinase activity of FLT3 have been developed, and two FLT3 inhibitors, midostaurin and gilteritinib, are currently used in clinics for AML patients [9,10]. While most investigations have concentrated on the kinase activity inhibition of FLT3 for AML therapeutics, several small molecules downregulating the FLT3 protein expression have been reported. These FLT3 downregulators exhibited the anti-proliferative effect on AML cell lines harboring FLT3 mutation. FLT3 protein level and the mechanism will be explained in this review
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