Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
Nat Commun. 2021 May 11;12(1):2621. doi: 10.1038/s41467-021-22924-4.
Cullin-RING E3 ligases (CRLs) regulate the turnover of approximately 20% of mammalian cellular proteins. Neddylation of individual cullin proteins is essential for the activation of each CRL. We report herein the discovery of DI-1548 and DI-1859 as two potent, selective and covalent DCN1 inhibitors. These inhibitors selectively inhibit neddylation of cullin 3 in cells at low nanomolar concentrations and are 2-3 orders of magnitude more potent than our previously reported reversible DCN1 inhibitor. Mass spectrometric analysis and co-crystal structures reveal that these compounds employ a unique mechanism of covalent bond formation with DCN1. DI-1859 induces a robust increase of NRF2 protein, a CRL3 substrate, in mouse liver and effectively protects mice from acetaminophen-induced liver damage. Taken together, this study demonstrates the therapeutic potential of selective inhibition of cullin neddylation.
Cullin-RING E3 连接酶（CRLs）调节大约 20%的哺乳动物细胞蛋白的周转。单个 cullin 蛋白的 neddylation 对于每个 CRL 的激活是必不可少的。我们在此报告了 DI-1548 和 DI-1859 的发现，它们是两种有效的、选择性的和共价的 DCN1 抑制剂。这些抑制剂以低纳摩尔浓度在细胞中选择性抑制 cullin 3 的 neddylation，并且比我们之前报道的可逆 DCN1 抑制剂强 2-3 个数量级。质谱分析和共晶体结构揭示了这些化合物与 DCN1 形成共价键的独特机制。DI-1859 诱导小鼠肝脏中 NRF2 蛋白（CRL3 的底物）的强烈增加，并有效保护小鼠免受对乙酰氨基酚引起的肝损伤。总之，这项研究证明了选择性抑制 cullin neddylation 的治疗潜力。
