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.