Abstract
Simple SummaryCell 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.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.
Highlights
Background and IntroductionEctoproteases have been initially defined as transmembrane proteins with an active catalytic site exposed to the external surface of the membrane, and are represented by peptidases and ADAMs [1]
Attention has been peculiarly focused on dipeptidyl peptidase 4 (DPP4, CD26), fibroblast activation protein alpha (FAP, Seprase), aminopeptidase N (APN, CD13), and ADAM17, whose deregulated expression in the tumour microenvironment (TME) is correlated with a malignant cancer phenotype [2,3,4,5,6,7,8,9,10,11,12,13,14] (Figure 1)
Most inhibitors developed so far against these ectoproteases showed no or limited anticancer activity in clinical trials, they are, crucial as starting points for designing improved ectoprotease targeting strategies for cancer therapy. In this Review, we critically summarize what is currently known about ectoprotease inhibitors and give an update on the newly developed drug candidates targeting these enzymes
Summary
Ectoproteases have been initially defined as transmembrane proteins with an active catalytic site exposed to the external surface of the membrane, and are represented by peptidases and ADAMs (a disintegrin and metalloprotease family) [1]. Attention has been peculiarly focused on dipeptidyl peptidase 4 (DPP4, CD26), fibroblast activation protein alpha (FAP, Seprase), aminopeptidase N (APN, CD13), and ADAM17 ( known as tumour necrosis factor-α-converting enzyme/TACE), whose deregulated expression in the tumour microenvironment (TME) is correlated with a malignant cancer phenotype (tumour cell growth, survival, metastasis, and tumour-associated angiogenesis) [2,3,4,5,6,7,8,9,10,11,12,13,14] (Figure 1).
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