Discovery of the selective and efficacious inhibitors of FLT3 mutations

Yanle Zhi; Baoquan Li; Chao Yao; Hongmei Li; Puzhou Chen; Jiyin Bao; Tianren Qin; Yue Wang; Tao Lu; Shuai Lu

doi:10.1016/j.ejmech.2018.06.010

Discovery of the selective and efficacious inhibitors of FLT3 mutations

Eur J Med Chem. 2018 Jul 15:155:303-315. doi: 10.1016/j.ejmech.2018.06.010. Epub 2018 Jun 5.

Authors

Yanle Zhi¹, Baoquan Li², Chao Yao², Hongmei Li², Puzhou Chen², Jiyin Bao², Tianren Qin³, Yue Wang², Tao Lu⁴, Shuai Lu⁵

Affiliations

¹ School of Sciences, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
² School of Sciences, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
³ School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China.
⁴ School of Sciences, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: lut163@163.com.
⁵ School of Sciences, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: lu_shuai@cpu.edu.cn.

PMID: 29894944
DOI: 10.1016/j.ejmech.2018.06.010

Abstract

Fms-like tyrosine kinase 3 (FLT3) is among the most frequently mutated protein in acute myeloid leukemia (AML), which has been confirmed as an important drug target for AML chemotherapy. Starting from the lead compound LT-106-175, a series of 1-H-pyrazole-3-carboxamide derivatives were synthesized to improve the FLT3 inhibitory potency and selectivity. Among them, compound 50 was identified as a highly potent and selective FLT3 inhibitor (IC₅₀ = 0.213 nM), which showed equal activities against various mutants of FLT3 including FLT3 (ITD)-D835V and FLT3 (ITD)-F691L that is resistant to quizartinib. Compound 50 also exhibited efficacy against the human AML cell line MV4-11 (IC₅₀ = 16.1 nM) harboring FLT3-ITD mutants. Inversely, compound 50 displayed no cytotoxicity to FLT3-independent cells, and the biochemical analyses showed that its effects were related to the inhibition of FLT3 signal pathways. Additionally, compound 50 induced apoptosis in MV4-11 cell as demonstrated by flow cytometry. Moreover, compound 50 showed enhanced metabolic stability. Altogether, it was concluded that compound 50 could be a promising FLT3 inhibitor for further developing therapeutic remedy of AML.

Keywords: AML; Acute myeloid; FLT3; FMS-Like tyrosine kinase 3 inhibitors; Leukemia.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Humans
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Molecular Structure
Mutation
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 / genetics

Substances

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