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

Journal of Medicinal Chemistry
2021.0

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 <b>14</b> 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 <b>14</b> were mediated through HDAC6 isoform inhibition as well as selective MAO-A and LSD1 inhibition. Moreover, the signatory feature of LSD1 inhibition by <b>14</b> in the context of H3K4ME2 accumulation was clearly evident from the results of western blot analysis. Gratifyingly, hydroxamic acid <b>14</b> 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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