MZH29 is a novel potent inhibitor that overcomes drug resistance FLT3 mutations in acute myeloid leukemia

B Xu; Y Zhao; X Wang; P Gong; W Ge

doi:10.1038/leu.2016.297

MZH29 is a novel potent inhibitor that overcomes drug resistance FLT3 mutations in acute myeloid leukemia

Leukemia. 2017 Apr;31(4):913-921. doi: 10.1038/leu.2016.297. Epub 2016 Oct 24.

Authors

B Xu¹, Y Zhao², X Wang¹, P Gong², W Ge¹

Affiliations

¹ National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.
² Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, Shenyang, China.

PMID: 27773927
DOI: 10.1038/leu.2016.297

Abstract

More than one-third of patients with acute myeloid leukemia (AML) harbor aberrant mutations in Fms-like tyrosine kinase 3 (FLT3). Among them, the internal tandem duplication (ITD) mutation predicts poor prognosis. MZH29 is a novel FLT3 inhibitor synthesized in our laboratory that showed that cellular and kinase assays sustained inhibitory effects on wild-type and mutant FLT3, including the FLT3-ITD, FLT3-D835H/Y/V and FLT3-K663Q mutants. More importantly, MZH29 retained its potent inhibitory effect against the FLT3-ITD/F691L mutation, a drug resistance mutation against the well-known FLT3 inhibitor, AC220. MZH29 is a type II FLT3 inhibitor that tolerated the F691L mutation in molecular docking studies. Oral administration of 10 mg/kg MZH29 caused complete tumor regression and extended survival in a mouse model of AML with less toxicity. Subsequent proteomics study revealed less proteome perturbation in the MZH29-treated group than in the AC220-treated group. MZH29 demonstrates potential and potent novel FLT3 inhibitory effects for the treatment of AML.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects
Apoptosis / genetics
Bone Marrow Transplantation
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Cell Survival / genetics
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm / genetics
Female
Gene Duplication
Humans
Leukemia, Myeloid, Acute / drug therapy
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / mortality
Male
Mice
Models, Molecular
Mutation*
Phenylurea Compounds / pharmacology*
Phenylurea Compounds / therapeutic use
Phosphorylation
Protein Conformation
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use
Quinolines / pharmacology*
Quinolines / therapeutic use
Signal Transduction / drug effects
Tandem Repeat Sequences
Xenograft Model Antitumor Assays
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
fms-Like Tyrosine Kinase 3 / chemistry
fms-Like Tyrosine Kinase 3 / genetics*
fms-Like Tyrosine Kinase 3 / metabolism

Substances

Antineoplastic Agents
MZH29 compound
Phenylurea Compounds
Protein Kinase Inhibitors
Quinolines
fms-Like Tyrosine Kinase 3