A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment
A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment
复制标题
DOI：
10.1038/nm.4474
复制
发表时间：
2018-02-01
期刊：
影响因子：
82.9
通讯作者：
Bence, Neil F.
中科院分区：
文献类型：
--
作者：
Hyer, Marc L.;Milhollen, Michael A.;Bence, Neil F.
泛素-蛋白酶体系统（UPS）包括负责维持细胞蛋白质稳态的酶网络。该途径的治疗潜力已通过许多UPS调节剂的临床成功得到验证，包括蛋白酶体抑制剂和免疫调节酰亚胺药物（IMiD）。在此，我们确定TAK-243（以前称为MLN 7243）是一种有效的、基于机制的泛素活化酶（UAE）小分子抑制剂，UAE是调节泛素结合级联的主要哺乳动物E1酶。TAK-243给药导致细胞泛素结合物耗竭，导致信号传导事件中断，诱导蛋白毒性应激，并损害细胞周期进展和DNA损伤修复途径。TAK-243给药导致癌细胞死亡，并且在主要人体异种移植研究中，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允许研究泛素生物学和评估UAE抑制作用，作为癌症治疗的新方法。
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.