卵巢癌（OC）是最致命的妇科肿瘤，确定新的治疗策略至关重要。在这里，我们测试了化合物 2c（4-羟基-2,6-双（4-硝基亚苄基）环己酮 2）的有效性。 2c 干扰半胱氨酸依赖性去泛素化酶 (DUB) UCHL5，从而影响泛素蛋白酶体依赖性蛋白质降解。在两种 OC 2D/3D 培养模型和小鼠异种移植模型中研究了 2c 表型/分子效应。此外，我们提出了 2c 与 DUB-UCHL5 相互作用的计算机模型。最后，我们测试了 2c 与多个接头缀合以生成可用于改善药物递送的 2c/衍生物的效果。2c 在 2D 和 3D 条件下均有效损害 OC 细胞系和原发性肿瘤细胞活力。其有效性在 OC 异种移植小鼠模型中得到证实。我们发现 2c 很可能通过与 DUB-UCHL5 相互作用来损害蛋白酶体活性并引发细胞凋亡。我们还提出了一种通过酶-抑制剂复合物的计算机评估与 DUB-UCHL5 相互作用的机制。 2c 还通过下调转录因子 E2F1 的水平来减少细胞生长。最终，2c 活性在与接头缀合后通常会保留。我们的数据强烈支持 2c/衍生物在 OC 中的潜在治疗价值。

The identification of novel therapeutic strategies for ovarian cancer (OC), the most lethal gynecological neoplasm, is of utmost urgency. Here, we have tested the effectiveness of the compound 2c (4-hydroxy-2,6-bis(4-nitrobenzylidene)cyclohexanone 2). 2c interferes with the cysteine-dependent deubiquitinating enzyme (DUB) UCHL5, thus affecting the ubiquitin-proteasome-dependent degradation of proteins.2c phenotypic/molecular effects were studied in two OC 2D/3D culture models and in a mouse xenograft model. Furthermore, we propose an in silico model of 2c interaction with DUB-UCHL5. Finally, we have tested the effect of 2c conjugated to several linkers to generate 2c/derivatives usable for improved drug delivery.2c effectively impairs the OC cell line and primary tumor cell viability in both 2D and 3D conditions. The effectiveness is confirmed in a xenograft mouse model of OC. We show that 2c impairs proteasome activity and triggers apoptosis, most likely by interacting with DUB-UCHL5. We also propose a mechanism for the interaction with DUB-UCHL5 via an in silico evaluation of the enzyme-inhibitor complex. 2c also reduces cell growth by down-regulating the level of the transcription factor E2F1. Eventually, 2c activity is often retained after the conjugation with linkers.Our data strongly support the potential therapeutic value of 2c/derivatives in OC.