Background - Cathepsin V (CatV) is potentially the most poorly understood cysteine cathepsin in humans. CatV was first identified from a cDNA library and expression was found to be restricted predominantly to the thymus, testis and corneal epithelium, making it one of the most stringently regulated cathepsins. The association with tumourigenesis was first identified in colorectal and breast carcinomas, with little expression observed in normal or peri-tumoural tissue. Further evidence for a role in tumourigenesis was derived from genomic analysis of invasive squamous cell carcinomas, where CatV expression correlated with malignancy. Although other family members have been shown to promote tumourigenesis, the function of CatV in cancer remains unresolved and it is essential that we understand its role, prior to developing therapeutic targeting strategies.
Inhibitor Development - The development of small-molecule inhibitors targeting individual cathepsins has historically been challenging, due to the high degree of homology within their active site. Using a molecular modelling approach, we have identified key structural differences within the active site of CatV. Interestingly, this research has revealed that CatV, also known as CatL2 due to high sequence homology, bares distinct differences in the substrate binding groove when compared to CatL. In fact, modelling and inhibitor screening data, has revealed that CatV more closely resembles CatS within its active site. This knowledge, coupled with SAR data has allowed for the identification of a first in class and truly selective Cathepsin V inhibitor that displays low nanomolar activity.