Legumain and Cathepsin B (LGMN and CTSB)

Legumain (LGMN) and Cathepsin B (CTSB) are lysosomal cysteine proteases that play pivotal roles in intracellular proteolysis, antigen processing, and tissue remodeling [1, 3]. Legumain, also known as asparaginyl endopeptidase (AEP), is unique for its strict specificity for asparaginyl bonds and its role as an upstream activator of other proteases, including Cathepsin B [1, 8]. Both enzymes are frequently overexpressed and secreted in the tumor microenvironment, where they facilitate cancer progression by degrading the extracellular matrix and promoting invasion, metastasis, and angiogenesis [5, 9]. Beyond oncology, they are implicated in neurodegenerative conditions such as Alzheimer's disease, where they contribute to the pathological processing of amyloid precursor protein and tau [11, 18]. In therapeutic development, Legumain and Cathepsin B are primarily utilized as molecular triggers for the selective activation of prodrugs and antibody-drug conjugates (ADCs), such as Brentuximab vedotin, which employ peptide linkers specifically cleaved by these enzymes to release cytotoxic payloads within target cells [14, 17]. Additionally, small molecule inhibitors like E64d and certain proton pump inhibitors are being explored to directly modulate their activity in cancer and inflammatory diseases [13, 22].

Other names

Asparaginyl endopeptidaseAEPδ-secretaseAPPCPAPPSCysteine protease 1LGMNCTSBProlegumainProcathepsin B

Protease-activated prodrug/ADC cleavage and enzyme inhibition