Ubiquitin activating enzyme (UAE) is a key enzyme responsible for ubiquitin conjugation in mammals. TAK-243 is a potent, small-molecule inhibitor of UAE with an IC50 value of 1 ± 0.2 nM. In HCT-116 cells, treatment with TAK-243 (0.01 - 1μΜ) dose-dependently reduced both polyubiquitin chains and mono-ubiquitylated histone H2B without affecting UAE protein levels. TAK-243 treatment also led to an accumulation of short-lived proteins, such as c-Jun, c-Myc, MCL1 and p53. In TAK-243-treated HCT-116 cells, a complete G2/M arrest was observed at the concentration of 0.05 μΜ. TAK-243 (0.01 - 1 μΜ) also induced the phosphorylation of kinase PERK, endoplasmic reticulum to nucleus signaling 1, and the accumulation of activating transcription factor 6. In Calu-6 cells, one-hour pretreatment of TAK-243 (1 μΜ) followed by UV irradiation resulted in persistent, unresolved DNA damage. TAK-243 showed an anti-proliferative effect in a panel of human cancer cell lines with variable EC50 values ranging from 0.006 to 1.31 μΜ. In mice bearing xenograft tumors (i.e. CWR22, SWU-DLCL2, and PHTX-132Lu) intravenous administration with TAK-243 (25 mg/kg/dose, 2 doses/week, 3 weeks) induced a robust antitumor activity response with tumor growth inhibition values ranging from 83 to 97[1].
作用机制
TAK-243 inhibits the catalytic activity of UAE via the formation of a TAK-243-ubiquitin adduct.
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