Dual FLT3 inhibitors: Against the drug resistance of acute myeloid leukemia in recent decade.

ABSTRACT

Acute myeloid leukemia (AML) is a malignant disease characterized by abnormal growth and differentiation of hematopoietic stem cells. Although the pathogenesis has not been fully elucidated, many specific gene mutations have been found in AML. Fms-like tyrosine kinase 3 (FLT3) is recognized as a drug target for the treatment of AML, and the activation mutations of FLT3 were found in about 30% of AML patients. Targeted inhibition of FLT3 receptor tyrosine kinase has shown promising results in the treatment of FLT3 mutation AML. Unfortunately, the therapeutic effects of FLT3 tyrosine kinase inhibitors used as AML monotherapy are usually accompanied by the high risk of resistance development within a few months after treatment. FLT3 dual inhibitors were generated with the co-inhibition of FLT3 and another target, such as CDK4, JAK2, MEK, Mer, Pim, etc., to solve the problems mentioned above. As a result, the therapeutic effect of the drug is significantly improved, while the toxic and side effects are reduced. Besides, the life quality of AML patients with FLT3 mutation has been effectively improved. In this paper, we reviewed the studies of dual FLT3 inhibitors that have been discovered in recent years for the treatment of AML.