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TAK-243 preferentially certain to UBA1 above the related E1 enzymes UBA2, UBA3, and UBA6 in intact AML cells. Inhibition of UBA1 with TAK-243 lessened levels of ubiquitylated proteins, amplified markers of proteotoxic strain and DNA injury tension. In vivo, TAK-243 diminished leukemic load and focused leukemic stem cells without evidence of toxicit