The ubiquitin-proteasome system (UPS) comprises a network of enzymes that is responsible for maintaining cellular protein homeostasis. The therapeutic potential of this pathway has been validated by the clinical successes of a number of UPS modulators, including proteasome inhibitors and immunomodulatory imide drugs (IMiDs). Here we identified TAK-243 (formerly known as MLN7243) as a potent, mechanism-based small-molecule inhibitor of the ubiquitin activating enzyme (UAE), the primary mammalian E1 enzyme that regulates the ubiquitin conjugation cascade. TAK-243 treatment caused depletion of cellular ubiquitin conjugates, resulting in disruption of signaling events, induction of proteotoxic stress, and impairment of cell cycle progression and DNA damage repair pathways. TAK-243 treatment caused death of cancer cells and, in primary human xenograft studies, demonstrated antitumor activity at tolerated doses. Due to its specificity and potency, TAK-243 allows for interrogation of ubiquitin biology and for assessment of UAE inhibition as a new approach for cancer treatment.

中文翻译：

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一种用于癌症治疗的泛素激活酶的小分子抑制剂。

泛素-蛋白酶体系统 (UPS) 包含负责维持细胞蛋白质稳态的酶网络。许多 UPS 调节剂的临床成功证实了该途径的治疗潜力，包括蛋白酶体抑制剂和免疫调节酰亚胺药物 (IMiD)。在这里，我们将 TAK-243（以前称为 MLN7243）鉴定为泛素激活酶 (UAE) 的有效、基于机制的小分子抑制剂，该酶是调节泛素偶联级联反应的主要哺乳动物 E1 酶。TAK-243 处理导致细胞泛素结合物的消耗，导致信号事件中断、蛋白毒性应激的诱导以及细胞周期进程和 DNA 损伤修复途径的损害。TAK-243 治疗导致癌细胞死亡，在主要的人类异种移植研究中，在耐受剂量下显示出抗肿瘤活性。由于其特异性和效力，TAK-243 允许对泛素生物学进行询问并评估作为癌症治疗新方法的阿联酋抑制。