State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, China.
State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, China; Pharm-X Center, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, China.
Neoplasia. 2022 Oct;32:100823. doi: 10.1016/j.neo.2022.100823. Epub 2022 Jul 27.
Inhibition of the NEDD8-activating enzyme (NAE), the key E1 enzyme in the neddylation cascade, has been considered an attractive anticancer strategy with the discovery of the first-in-class NAE inhibitor, MLN4924. In this study, we identified SOMCL-19-133 as a highly potent, selective, and orally available NAE inhibitor, which is an analog to AMP. It effectively inhibited NAE with an IC value of 0.36 nM and exhibited more than 2855-fold selectivity over the closely related Ubiquitin-activating enzyme (UAE). It is worth noting that treatment with SOMCL-19-133 prominently inhibited Cullin neddylation and delayed the turnover of a panel of Cullin-RING ligases (CRLs) substrates (e.g., Cdt1, p21, p27, and Wee1) at lower effective concentrations than that of MLN4924, subsequently caused DNA damage and Chk1/Chk2 activation, and thus triggered cell cycle arrest and apoptosis. Moreover, SOMCL-19-133 exhibited potent antiproliferative activity against a broad range of human tumor cell lines (mean IC 201.11 nM), which was about 5.31-fold more potent than that of MLN4924. In vivo, oral delivery treatments with SOMCL-19-133, as well as the subcutaneous injection, led to significant tumor regression in mouse xenograft models. All of the treatments were well tolerated on a continuous daily dosing schedule. Compared with MLN4924, SOMCL-19-133 had a 5-fold higher peak plasma concentration, lower plasma clearance, and a 4-fold larger area under the curve (AUC). In conclusion, SOMCL-19-133 is a promising preclinical candidate for treating cancers owing to its profound in vitro and in vivo efficacy and favorable pharmacokinetic properties.
抑制 NEDD8-激活酶（NAE），即 neddylation 级联中的关键 E1 酶，已被认为是一种有吸引力的抗癌策略，随着首个 NAE 抑制剂 MLN4924 的发现。在这项研究中，我们鉴定出 SOMCL-19-133 是一种高效、选择性和可口服的 NAE 抑制剂，它是 AMP 的类似物。它有效地抑制 NAE，IC 值为 0.36 nM，对密切相关的泛素激活酶（UAE）的选择性超过 2855 倍。值得注意的是，SOMCL-19-133 的治疗明显抑制了 Cullin 的 neddylation，并在比 MLN4924 更低的有效浓度下延迟了一组 Cullin-RING 连接酶（CRLs）底物（例如 Cdt1、p21、p27 和 Wee1）的周转，随后导致 DNA 损伤和 Chk1/Chk2 激活，从而引发细胞周期停滞和细胞凋亡。此外，SOMCL-19-133 对广泛的人类肿瘤细胞系表现出强大的增殖抑制活性（平均 IC 201.11 nM），比 MLN4924 强约 5.31 倍。在体内，SOMCL-19-133 的口服给药以及皮下注射在小鼠异种移植模型中导致显著的肿瘤消退。所有的治疗方案在连续每日给药方案中都有良好的耐受性。与 MLN4924 相比，SOMCL-19-133 的峰值血浆浓度高 5 倍，血浆清除率低，曲线下面积（AUC）大 4 倍。总之，SOMCL-19-133 是一种很有前途的临床前候选药物，因为它具有深刻的体外和体内疗效和良好的药代动力学特性，可用于治疗癌症。
