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Molecular targets for therapy

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

Leukemia volume 31, pages 913–921 (2017)Cite this article

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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.

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Acknowledgements

We thank Qingsong Liu’s group for proving the cell lines stably expressed the FLT3 mutants. We thank Professor Haiteng Deng and the Protein Chemistry Facility at the Center for Biomedical Analysis of Tsinghua University for the sample analysis. We also thank Yu Wang for sorting the compounds chemical data. This study was supported by the Novo Nordisk Union Diabetes Research Talent Fund 2013 to WG, CAMS Initiative for Innovative Medicine (CAMS-I2M) 2016-I2M-3 to WG, PUMC Youth Fund, and the Fundamental Research Funds for the Central Universities (3332015020 to BHX).

Author contributions

BX and WG designed the studies and wrote the paper. BX performed the experiments and docking. YZ and PG designed and synthesized the chemical structures.

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Author notes

  1. B Xu and Y Zhao: These authors contributed equally to this work.

Authors and 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

    B Xu, X Wang & W Ge

  2. Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, Shenyang, China

    Y Zhao & P Gong

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  1. B Xu
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Correspondence to P Gong or W Ge.

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The authors declare that they own the intellectual property of the new synthesized compound in this paper. No additional conflicts of interest exist.

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Xu, B., Zhao, Y., Wang, X. et al. MZH29 is a novel potent inhibitor that overcomes drug resistance FLT3 mutations in acute myeloid leukemia. Leukemia 31, 913–921 (2017). https://doi.org/10.1038/leu.2016.297

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