Discovery of\nNovel\n5‑Cyano-3-phenylindole-Based\nLSD1/HDAC Dual Inhibitors for Colorectal Cancer Treatment

The\ndual inhibition of histone lysine-specific demethylase 1 (LSD1)\nand histone deacetylase (HDAC) has emerged as a promising strategy\nfor cancer therapy. In this study, we report the discovery of novel\n5-cyano-3-phenylindole-based LSD1/HDAC dual inhibitors, evaluated\nthrough both in vitro and in vivo assays. Among these inhibitors,\ncompound <b>20c</b> was identified as particularly potent, exhibiting\nhigh inhibitory activity against LSD1 (IC<sub>50</sub> = 39.0 nM)\nand HDAC1/2/3/6/8 (IC<sub>50</sub> = 1.4, 1.0, 1.3, 2.9, and 16.0\nnM, respectively). Compound <b>20c</b> effectively modulated\nthe expression of biomarkers associated with LSD1 and HDAC inhibition\nand demonstrated superior antiproliferative activity compared to SAHA\nand 4SC-202 across multiple colorectal cancer cell lines. Following\npharmacokinetic studies, <b>20c</b> was further assessed in\nHCT-116 and HT-29 xenograft mouse models. It demonstrated significantly\nenhanced antitumor efficacy compared to SAHA, without causing observable\ntoxicity. These findings highlight the potential of LSD1/HDAC dual\ninhibitors for the treatment of malignant cancers.