2. Academic Validation
  3. Installation of Pargyline, a LSD1 Inhibitor, in the HDAC Inhibitory Template Culminated in the Identification of a Tractable Antiprostate Cancer Agent

Installation of Pargyline, a LSD1 Inhibitor, in the HDAC Inhibitory Template Culminated in the Identification of a Tractable Antiprostate Cancer Agent

  • J Med Chem. 2021 Dec 23;64(24):17824-17845. doi: 10.1021/acs.jmedchem.1c00966.
Ritu Ojha 1,  I-Chung Chen 1,  Chien-Ming Hsieh 1 2,  Kunal Nepali 1 2,  Row-Wen Lai 1,  Kai-Cheng Hsu 3 2 4,  Tony Eight Lin 5,  Shiow-Lin Pan 3 2 4,  Mei-Chuan Chen 1 2 4 6 7,  Jing-Ping Liou 1 2
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110031, Taiwan.
  • 2 TMU Research Center of Drug Discovery, Taipei Medical University, Taipei 110031, Taiwan.
  • 3 Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110031, Taiwan.
  • 4 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 110031, Taiwan.
  • 5 Master Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110031, Taiwan.
  • 6 Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei 110031, Taiwan.
  • 7 Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei 110031, Taiwan.
PMID: 34908406 DOI: 10.1021/acs.jmedchem.1c00966
Abstract

Pragmatic insertion of pargyline, a LSD1 inhibitor, as a surface recognition part in the HDAC inhibitory pharmacophore was planned in pursuit of furnishing potent antiprostate Cancer agents. Resultantly, compound 14 elicited magnificent cell growth inhibitory effects against the PC-3 and DU-145 cell lines and led to remarkable suppression of tumor growth in human prostate PC-3 and DU-145 xenograft nude mouse models. The outcome of the enzymatic assays ascertained that the substantial antiproliferative effects of compound 14 were mediated through HDAC6 isoform inhibition as well as selective MAO-A and LSD1 inhibition. Moreover, the signatory feature of LSD1 inhibition by 14 in the context of H3K4ME2 accumulation was clearly evident from the results of western blot analysis. Gratifyingly, hydroxamic acid 14 demonstrates good human hepatocytic stability and good oral bioavailability in rats and exhibits enough promise to emerge as a therapeutic for the treatment of prostate Cancer in the near future.

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