Journal
PHARMACEUTICALS
Volume 15, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/ph15030320
Keywords
fms-like tyrosine kinase 3; target protein degrader; heat shock protein 90; ubiquitin proteasome system
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Funding
- National Research Foundation of Korea [2021R1A2C1007790]
- National Research Foundation of Korea [2021R1A2C1007790] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Target protein degraders are a new paradigm in small molecule drug discovery, important for treating acute myeloid leukemia. Strategies to overcome resistance to current FLT3 kinase inhibitors are needed. Small molecules that downregulate FLT3 protein level have shown antileukemic effects.
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.
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