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

Ting Yuan; Baowen Qi; Zhongliang Jiang; Wenjuan Dong; Lei Zhong; Lan Bai; Rongsheng Tong; Jiying Yu; Jianyou Shi

doi:10.1016/j.ejmech.2019.06.002

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

Eur J Med Chem. 2019 Sep 15:178:468-483. doi: 10.1016/j.ejmech.2019.06.002. Epub 2019 Jun 5.

Authors

Ting Yuan¹, Baowen Qi², Zhongliang Jiang³, Wenjuan Dong¹, Lei Zhong¹, Lan Bai¹, Rongsheng Tong¹, Jiying Yu⁴, Jianyou Shi⁵

Affiliations

¹ Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, Chengdu, 610072, China.
² College of Pharmacy and Biological Engineering, Chengdu University, Chengdu, 610106, China.
³ Miller School of Medicine, University of Miami, Miami, Florida, 33136, USA.
⁴ Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, Chengdu, 610072, China. Electronic address: yujiying@163.com.
⁵ Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, Chengdu, 610072, China. Electronic address: shijianyoude@126.com.

PMID: 31207462
DOI: 10.1016/j.ejmech.2019.06.002

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.

Keywords: Acute myeloid leukemia; Drug resistance; Dual inhibitors; FLT3.

Publication types

Review

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm / drug effects*
Drug Screening Assays, Antitumor
Humans
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
fms-Like Tyrosine Kinase 3 / metabolism

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
FLT3 protein, human
fms-Like Tyrosine Kinase 3