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

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.