Hepsin is a type II transmembrane serine protease (TTSP) that plays a crucial
role in cell growth and development. Hepsin is highly expressed in prostate cancer (PCa)
and associated with its progression and metastasis. Therefore, it has been considered as an
attractive biomarker of PCa. Recently, low molecular weight inhibitors targeting hepsin
have been developed. Based on the key chemical scaffold, they can be classified into four
classes: Indolecarboxamidines, benzamidines, peptide-based analogs, and 2,3-dihydro-
1H-perimidines. In this review, we discuss design strategy, structure-activity relationship
(SAR), and binding mode of the four classes of hepsin inhibitors.