Disease-related phenotypic assays enable unbiased discovery of novel bioactive small molecules and may provide novel insights into physiological systems and unprecedented molecular modes of action (MMOA). Herein, we report the identification and characterization of epoxykynin, a potent inhibitor of the soluble epoxide hydrolase (sEH). Epoxykynin was discovered by means of a cellular assay monitoring modulation of kynurenine (Kyn) levels in BxPC-3 cells upon stimulation with the cytokine interferon-γ (IFN-γ) and subsequent target identification employing affinity-based chemical proteomics. Increased Kyn levels are associated with immune suppression in the tumor microenvironment and, thus, the Kyn pathway and its key player indoleamine 2,3-dioxygenase 1 (IDO1) are appealing targets in immuno-oncology. However, targeting IDO1 directly has led to limited success in clinical investigations, demonstrating that alternative approaches to reduce Kyn levels are in high demand. We uncover a cross-talk between sEH and the Kyn pathway that may provide new opportunities to revert cancer-induced immune tolerance.

中文翻译：

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发现 sEH 抑制剂 Epoxykynin 作为有效的犬尿氨酸途径调节剂

疾病相关的表型测定能够公正地发现新型生物活性小分子，并可能为生理系统和前所未有的分子作用模式（MMOA）提供新的见解。在此，我们报告了环氧奇宁（epoxykynin）的鉴定和表征，环氧奇宁是可溶性环氧化物水解酶（sEH）的有效抑制剂。环氧犬蛋白是通过细胞测定法监测 BxPC-3 细胞中受细胞因子干扰素-γ (IFN-γ) 刺激后犬尿氨酸 (Kyn) 水平的调节以及随后采用基于亲和力的化学蛋白质组学进行靶标识别而发现的。 Kyn 水平升高与肿瘤微环境中的免疫抑制相关，因此，Kyn 通路及其关键参与者吲哚胺 2,3-双加氧酶 1 (IDO1) 是免疫肿瘤学中颇具吸引力的靶点。然而，直接靶向 IDO1 在临床研究中取得的成功有限，这表明降低 Kyn 水平的替代方法的需求很高。我们发现 sEH 和 Kyn 通路之间的相互作用可能为恢复癌症诱导的免疫耐受提供新的机会。