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Acute myeloid leukemia

Preclinical evaluation of the selective small-molecule UBA1 inhibitor, TAK-243, in acute myeloid leukemia

Leukemia volume 33, pages 37–51 (2019)Cite this article

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Abstract

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy for which new therapeutic approaches are required. One such potential therapeutic strategy is to target the ubiquitin-like modifier-activating enzyme 1 (UBA1), the initiating enzyme in the ubiquitylation cascade in which proteins are tagged with ubiquitin moieties to regulate their degradation or function. Here, we evaluated TAK-243, a first-in-class UBA1 inhibitor, in preclinical models of AML. In AML cell lines and primary AML samples, TAK-243 induced cell death and inhibited clonogenic growth. In contrast, normal hematopoietic progenitor cells were more resistant. TAK-243 preferentially bound to UBA1 over the related E1 enzymes UBA2, UBA3, and UBA6 in intact AML cells. Inhibition of UBA1 with TAK-243 decreased levels of ubiquitylated proteins, increased markers of proteotoxic stress and DNA damage stress. In vivo, TAK-243 reduced leukemic burden and targeted leukemic stem cells without evidence of toxicity. Finally, we selected populations of AML cells resistant to TAK-243 and identified missense mutations in the adenylation domain of UBA1. Thus, our data demonstrate that TAK-243 targets AML cells and stem cells and support a clinical trial of TAK-243 in this patient population. Moreover, we provide insight into potential mechanisms of acquired resistance to UBA1 inhibitors.

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Acknowledgements

We thank Dr. James Brownell from Takeda Pharmaceuticals for critical review of the biochemical aspects of the manuscript, and Dr. Michael Sintchak for invaluable scientific advice. We also thank Jill Flewelling and Francesca Pulice at Princess Margaret Cancer Centre for administrative assistance. This work was supported by a research grant from Takeda Pharmaceuticals Inc., the Princess Margaret Cancer Centre Foundation, Canadian Institutes of Health Research (CIHR), the Ontario Institute of Cancer Research, the Canada Research Chairs program, The Ontario Ministry of Research and Innovation, and The Ministry of Long Term Health and Planning in the Province of Ontario. A.D.S. holds the Barbara Baker Chair in Leukemia and Related Diseases. S.H.B. is supported by Ontario Trillium Scholarship, Department of Medical Biophysics fellowship and GSEF scholarship from the Faculty of Medicine, University of Toronto. IHC staining was done in the Applied Molecular Profiling Laboratory (AMPL) facility and imaging was done in the Advanced Optical Microscopy Facility (AOMF) at Princess Margaret Cancer Centre.

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Authors and Affiliations

  1. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

    Samir H. Barghout, Parasvi S. Patel, Xiaoming Wang, G. Wei Xu, Simon Kavanagh, Ondrej Halgas, Sara F. Zarabi, Marcela Gronda, Rose Hurren, Danny V. Jeyaraju, Neil MacLean, Mark D. Minden, Emil F. Pai, Razq Hakem & Aaron D. Schimmer

  2. Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Samir H. Barghout, Parasvi S. Patel, Sara F. Zarabi, Mark D. Minden, Emil F. Pai, Razq Hakem & Aaron D. Schimmer

  3. Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Ondrej Halgas & Emil F. Pai

  4. Department of Laboratory Medicine, University Health Network, Toronto, ON, Canada

    Shawn Brennan & Adam C. Smith

  5. Oncology Drug Discovery Unit, Takeda Pharmaceuticals International Co., Cambridge, MA, USA

    Marc L. Hyer, Allison Berger, Tary Traore & Michael Milhollen

  6. Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Adam C. Smith

  7. Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Brazil

    Adam C. Smith

  8. Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Emil F. Pai

  9. Agios Pharmaceuticals, Cambridge, MA, USA

    Marc L. Hyer

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  1. Samir H. Barghout
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Correspondence to Aaron D. Schimmer.

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Conflict of interest

A.D.S. received research funding from Takeda Pharmaceutical Company Limited. A.B., T.T., and M.M. are employees of Takeda Pharmaceutical Company Limited, and M.L.H. was employed by Takeda Pharmaceutical Company Limited at the time of the study.

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Barghout, S.H., Patel, P.S., Wang, X. et al. Preclinical evaluation of the selective small-molecule UBA1 inhibitor, TAK-243, in acute myeloid leukemia. Leukemia 33, 37–51 (2019). https://doi.org/10.1038/s41375-018-0167-0

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