2. Academic Validation
  3. Syntheses of LSD1/HDAC Inhibitors with Demonstrated Efficacy against Colorectal Cancer: In Vitro and In Vivo Studies Including Patient-Derived Organoids

Syntheses of LSD1/HDAC Inhibitors with Demonstrated Efficacy against Colorectal Cancer: In Vitro and In Vivo Studies Including Patient-Derived Organoids

  • J Med Chem. 2024 Oct 10;67(19):17207-17225. doi: 10.1021/acs.jmedchem.4c01098.
Po-Yu Chou 1,  Mei-Jung Lai 2,  Kelvin K Tsai 3 4,  Li-Hsin Cheng 4,  Yi-Wen Wu 5,  Mei-Chuan Chen 1 2 6 7 8,  Shiow-Lin Pan 2 5 9 6 10,  Hsiu-O Ho 1,  Kunal Nepali 1 2 6,  Jing-Ping Liou 1 2 9 6
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
  • 2 TMU Research Center for Drug Discovery, Taipei Medical University, Taipei 110, Taiwan.
  • 3 Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
  • 4 Organoids Technology Core, Taipei Medical University, Taipei 110, Taiwan.
  • 5 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
  • 6 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 110031, Taiwan.
  • 7 Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
  • 8 Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei 110, Taiwan.
  • 9 TMU Research Center of Cancer Translational Medicine, Taipei 110, Taiwan.
  • 10 Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
PMID: 39320444 DOI: 10.1021/acs.jmedchem.4c01098
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.

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