Discovery of Novel 5‑Cyano-3-phenylindole-Based LSD1/HDAC Dual Inhibitors for Colorectal Cancer Treatment

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.

组蛋白赖氨酸特异性去甲基化酶1（histone lysine-specific demethylase 1, LSD1）与组蛋白去乙酰化酶（histone deacetylase, HDAC）的双重抑制已成为极具前景的癌症治疗策略。本研究报道了一类新型的基于5-氰基-3-苯基吲哚的LSD1/HDAC双重抑制剂，并通过体外及体内实验完成了活性评价。在该系列抑制剂中，化合物20c被鉴定为活性尤为突出的分子，其对LSD1具有极强的抑制活性（半数抑制浓度IC50=39.0 nM），对HDAC1/2/3/6/8的IC50值分别为1.4、1.0、1.3、2.9和16.0 nM。化合物20c可有效调控与LSD1和HDAC抑制相关的生物标志物表达，且在多种结直肠癌细胞系中，其抗增殖活性优于SAHA与4SC-202。完成药代动力学研究后，我们进一步在HCT-116与HT-29异种移植小鼠模型中对化合物20c进行了评估。结果显示，相较于SAHA，化合物20c的抗肿瘤疗效显著提升，且未观察到明显毒副作用。上述研究结果充分凸显了LSD1/HDAC双重抑制剂在恶性肿瘤治疗中的应用潜力。