葡萄膜黑色素瘤（UM）是一种高度侵袭性的疾病，治疗选择很少。我们之前证明了 mUM 的特点是高氧化磷酸化 (OXPHOS)。在这里，我们测试了亚咪酮的抗肿瘤、信号传导和代谢作用，亚咪酮是 CLPP 激活剂，可间接抑制 OXPHOS，并已证明对患者的安全性。我们评估了 UM 患者样本中的 CLPP 表达。我们测试了亚咪啶酮（ONC201 和 ONC212）对 UM 细胞系的体外生长、存活、信号传导和代谢的影响，以及 UM 肝转移模型中的体内治疗效果。在原发性和 mUM 患者样本中检测到 CLPP 表达。 ONC201 和 212 减少 OXPHOS 效应子，抑制细胞生长和迁移，并在体外诱导人 UM 细胞系凋亡。 ONC212 抑制 OXPHOS，增加代谢应激和细胞凋亡途径，抑制氨基酸代谢，并诱导细胞死亡相关的脂质。 ONC212 还在两个 UM 肝转移模型中降低了肿瘤负荷并提高了体内存活率。亚咪酮是 mUM 进一步测试和开发的有前途的策略。© 2024。作者。

Uveal melanoma (UM) is a highly aggressive disease with very few treatment options. We previously demonstrated that mUM is characterized by high oxidative phosphorylation (OXPHOS). Here we tested the anti-tumor, signaling and metabolic effects of imipridones, which are CLPP activators, which inhibit OXPHOS indirectly and have demonstrated safety in patients.We assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201 and ONC212) on the growth, survival, signaling and metabolism of UM cell lines in vitro, and for therapeutic efficacy in vivo in UM liver metastasis models.CLPP expression was detected in primary and mUM patient samples. ONC201 and 212 decreased OXPHOS effectors, inhibited cell growth and migration, and induced apoptosis in human UM cell lines in vitro. ONC212 inhibited OXPHOS, increased metabolic stress and apoptotic pathways, inhibited amino acid metabolism, and induced cell death-related lipids. ONC212 also decreased tumor burden and increased survival in vivo in two UM liver metastasis models.Imipridones are a promising strategy for further testing and development in mUM.© 2024. The Author(s).