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Syntheses of LSD1/HDAC Inhibitors with Demonstrated Efficacy against Colorectal Cancer: In Vitro and In Vivo Studies
Po-Yu Chou1, Mei-Jung Lai2, Kelvin K Tsai3,4
1School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
Abstract:
Precedential evidence ascertaining the overexpression of LSD1 and HDACs in colorectal cancer spurred us to design a series of dual LSD1-HDAC inhibitors. Capitalizing on the modular nature of the three-component HDAC inhibitory model, tranylcypromine as a surface recognition motif was appended to zinc-binding motifs via diverse linkers. A compendium of hydroxamic acids was generated and evaluated for in vitro cytotoxicity against HCT-116 cells (human colorectal cancer cell lines). The most potent cell growth inhibitor 2 (GI50 = 0.495 μMm HCT-116 cells) shows promising anticancer effects by reducing colony formation and inducing cell cycle arrest in HCT-116 cells. It exhibits preferential inhibition of HDAC6, along with potent inhibition of LSD1 compared to standard inhibitors. Moreover, Compound 2 upregulates acetyl-tubulin, acetyl-histone H3, and H3K4me2, indicative of LSD1 and HDAC inhibition. In vivo, it demonstrates significant antitumor activity against colorectal cancer, better than irinotecan, and effectively inhibits growth in patient-derived CRC organoids.
Insights
Researchers developed novel dual lysine-specific demethylase 1 (LSD1) and histone deacetylase (HDAC) inhibitors for colorectal cancer. Compound 2 demonstrated significant in vitro and in vivo antitumor activity, outperforming irinotecan.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) are overexpressed in colorectal cancer (CRC).
- Targeting these enzymes offers a potential therapeutic strategy for CRC treatment.
Purpose of the Study:
- To design and synthesize novel dual LSD1-HDAC inhibitors.
- To evaluate the in vitro and in vivo efficacy of these inhibitors against colorectal cancer.
Main Methods:
- A series of hydroxamic acid-based dual LSD1-HDAC inhibitors were synthesized using a three-component model.
- In vitro cytotoxicity was assessed against HCT-116 cells.
- In vivo antitumor activity was evaluated in a CRC model and patient-derived organoids.
Main Results:
- Compound 2 exhibited potent in vitro cytotoxicity (GI50 = 0.495 μM) against HCT-116 cells, reducing colony formation and inducing cell cycle arrest.
- Compound 2 preferentially inhibited HDAC6 and potently inhibited LSD1, upregulating acetyl-tubulin, acetyl-histone H3, and H3K4me2.
- In vivo, Compound 2 demonstrated significant antitumor activity superior to irinotecan and inhibited patient-derived CRC organoid growth.
Conclusions:
- Dual LSD1-HDAC inhibition represents a promising therapeutic approach for colorectal cancer.
- Compound 2 is a potent dual inhibitor with significant in vitro and in vivo anticancer effects, warranting further clinical investigation.
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