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

Ritu Ojha, I. Chung Chen, Chien Ming Hsieh, Kunal Nepali, Row Wen Lai, Kai Cheng Hsu, Tony Eight Lin, Shiow Lin Pan, Mei Chuan Chen, Jing Ping Liou

研究成果: 雜誌貢獻文章同行評審

摘要

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.

原文英語
頁(從 - 到)17824-17845
頁數22
期刊Journal of Medicinal Chemistry
64
發行號24
DOIs
出版狀態接受/付印 - 2021

ASJC Scopus subject areas

  • 分子醫學
  • 藥物發現

指紋

深入研究「Installation of Pargyline, a LSD1 Inhibitor, in the HDAC Inhibitory Template Culminated in the Identification of a Tractable Antiprostate Cancer Agent」主題。共同形成了獨特的指紋。

引用此