2. Academic Validation
  3. Discovery of Novel 5-Cyano-3-phenylindole-Based LSD1/HDAC Dual Inhibitors for Colorectal Cancer Treatment

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

  • J Med Chem. 2024 Nov 28;67(22):20172-20202. doi: 10.1021/acs.jmedchem.4c01524.
Hui-Juan Zhu 1,  Hui-Min Zhou 1,  Xiao-Xiao Zhou 1,  Shi-Jie Li 1,  Meng-Jie Zheng 1,  Zhen Xu 1,  Wen-Jing Dai 1,  Yi-Bo Ban 1,  Meng-Yao Zhang 1,  Yi-Zhe Zhang 1,  Jia-Rui Lu 2,  Yong-Tao Xu 2,  Sai-Qi Wang 3,  Xiao-Jing Shi 4,  Ying-Chao Duan 1
Affiliations

Affiliations

  • 1 School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, PR China.
  • 2 School of Medical Engineering, Xinxiang Medical University, Xinxiang, Henan 453003, PR China.
  • 3 Department of Oncology, Henan Province Engineering Research Center for of Intractable Digestive Tract Tumor Precision Therapy & Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan Province 450008, PR China.
  • 4 Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Laboratory Animal Center, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province 450052, PR China.
PMID: 39540222 DOI: 10.1021/acs.jmedchem.4c01524
Abstract

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.

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