The dual inhibition of histone lysine-specific demethylase 1 (LSD1) and histone deacetylase (HDAC) has emerged as a promising strategy for cancer therapy. In this study, we report the discovery of novel 5-cyano-3-phenylindole-based LSD1/HDAC dual inhibitors, evaluated through both in vitro and in vivo assays. Among these inhibitors, compound 20c was identified as particularly potent, exhibiting high inhibitory activity against LSD1 (IC₅₀ = 39.0 nM) and HDAC1/2/3/6/8 (IC₅₀ = 1.4, 1.0, 1.3, 2.9, and 16.0 nM, respectively). Compound 20c effectively modulated the expression of biomarkers associated with LSD1 and HDAC inhibition and demonstrated superior antiproliferative activity compared to SAHA and 4SC-202 across multiple colorectal cancer cell lines. Following pharmacokinetic studies, 20c was further assessed in HCT-116 and HT-29 xenograft mouse models. It demonstrated significantly enhanced antitumor efficacy compared to SAHA, without causing observable toxicity. These findings highlight the potential of LSD1/HDAC dual inhibitors for the treatment of malignant cancers.

中文翻译：

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发现基于 5-氰基-3-苯基吲哚的新型 LSD1/HDAC 双重抑制剂治疗结直肠癌


组蛋白赖氨酸特异性脱甲基酶 1 （LSD1） 和组蛋白脱乙酰酶 （HDAC） 的双重抑制已成为一种很有前途的癌症治疗策略。在这项研究中，我们报告了通过体外和体内测定评估的新型基于 5-氰基-3-苯基吲哚的 LSD1/HDAC 双重抑制剂的发现。在这些抑制剂中，化合物 20c 被鉴定为特别有效，对 LSD1 （IC₅₀ = 39.0 nM） 和 HDAC1/2/3/6/8 （IC₅₀ = 1.4、1.0、1.3、2.9 和 16.0 nM）表现出高抑制活性。化合物 20c 有效调节与 LSD1 和 HDAC 抑制相关的生物标志物的表达，与SAHA和4SC-202相比，在多种结直肠癌细胞系中表现出优异的抗增殖活性。在药代动力学研究之后，在 HCT-116 和 HT-29 异种移植小鼠模型中进一步评估了 20c。与 SAHA 相比，它显示出显着增强的抗肿瘤功效，而不会引起可观察到的毒性。这些发现突出了 LSD1/HDAC 双重抑制剂治疗恶性癌症的潜力。