Hepsin, a type II transmembrane serine protease, is an attractive protein which acts as a potential therapeutic and diagnostic biomarker of prostate cancer because it is highly up-regulated in prostate cancer and promotes the progression and metastasis of prostate cancer. Our efforts to develop novel hepsin inhibitors were based on the reported hepsin inhibitors such as amidine-functionalized indole analogs and guanidine-containing peptides. Novel amidine/guanidine-containing analogs as hepsin inhibitors were designed and synthesized. Most of the synthesized compounds showed <i>in vitro</i> inhibitory activity against hepsin in the submicromolar ranges. Based on the structure-activity relationship (SAR) studies of amidine/guanidine-derived analogs, the most potent hepsin was conjugated with optical dyes such as SulfoCy7 and Bodipy for in vitro and in vivo imaging studies. <i>In vitro</i> cell uptake and in vivo preliminary optical imaging experiments exhibited moderately selective binding and retention in high hepsin-expressing cells and tumors as compared with low hepsin-expressing cells. The identified hepsin inhibitors have a potential to be utilized as lead compounds for the development of novel prostate cancer diagnostic/therapeutic agents.

Hepsin-targeted ligands for prostate cancer imaging and therapy

253rd National Meeting (2017)

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