Targeting Dipeptidyl Peptidase-4 (DPP-4) and Fibroblast Activation Protein (FAP) for Diabetes and Cancer Therapy
In recent years, the dipeptidyl peptidase-4 (DPP-4) enzyme family has created intense pharmaceutical interest. DPP-4 inhibitors have proven successful as a therapy for the growing type 2 diabetes epidemic and have potential to treat other diseases. A large number of recently developed DPP-4 inhibitors are in various phases of clinical development, with four gliptin class inhibitors already in clinical use. The unique distribution of Fibroblast Activation Protein (FAP), the closest relative of DPP-4, has led to numerous investigations of it as a target and marker for epithelial cancers. The roles of the newer members, DPP-8 and DPP-9, are yet to be fully characterized, but early evidence suggests possible roles in various aspects of cell biology and disease. There are a number of favorable circumstances that have contributed to the therapeutic approaches of targeting DPP-4 and FAP. Specific targeting of DPP-4 and FAP is made easier by the small size of this enzyme family and several structural differences at their active sites. Additionally, observations over the past decade that the DPP-4 and FAP gene knockout mice are healthy suggests that selective inhibition of each of these proteases would be safe, and this is reflected in the excellent safety profiles of the DPP-4-selective gliptins. These proteins also have interesting extra-enzymatic activities that are expected to be retained in the presence of protease inhibition. This feature also points to a low likelihood of off-target effects. Thus, an overall understanding of DPP-4 and FAP structure–function relationships, distribution, and enzymatic and extra-enzymatic biological roles provides an insight into their therapeutic usefulness as disease targets.