• 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, Shawn Brennan, Marc L Hyer, Allison Berger, Tary Traore, Michael Milhollen, Adam C Smith, Mark D Minden, Emil F Pai, Razq Hakem, and Aaron D Schimmer.
• Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
• Leukemia. 2019 Jan 1; 33 (1): 37-51.

AbstractAcute 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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