Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

SIMPLE SUMMARY: Cell surface proteases (so-called ectoproteases) are associated with cancer, and their targeting may confer valuable options for the improvement of cancer treatment outcome. Over the past 20 years, the permanent development of a multitude of inhibitors against several ectoproteases (including DPP4, FAP, APN, ADAM17, MMP2, and MMP9) has made it into clinical evaluation in haematological and solid tumours. Among them, a few show some efficacy, albeit limited, to cure cancer in the near future. This Review summarizes the efforts thus far undertaken in the development of ectoprotease inhibitors and highlights new directions for targeting ectoproteases as an additional weapon in the fight against cancer. ABSTRACT: Cell surface proteases (also known as ectoproteases) are transmembrane and membrane-bound enzymes involved in various physiological and pathological processes. Several members, most notably dipeptidyl peptidase 4 (DPP4/CD26) and its related family member fibroblast activation protein (FAP), aminopeptidase N (APN/CD13), a disintegrin and metalloprotease 17 (ADAM17/TACE), and matrix metalloproteinases (MMPs) MMP2 and MMP9, are often overexpressed in cancers and have been associated with tumour dysfunction. With multifaceted actions, these ectoproteases have been validated as therapeutic targets for cancer. Numerous inhibitors have been developed to target these enzymes, attempting to control their enzymatic activity. Even though clinical trials with these compounds did not show the expected results in most cases, the field of ectoprotease inhibitors is growing. This review summarizes the current knowledge on this subject and highlights the recent development of more effective and selective drugs targeting ectoproteases among which small molecular weight inhibitors, peptide conjugates, prodrugs, or monoclonal antibodies (mAbs) and derivatives. These promising avenues have the potential to deliver novel therapeutic strategies in the treatment of cancers.