Design of Inhibitors of the Human Fibroblast Activation Protein α as a Strategy to Hinder Metastasis and Angiogenesis

In many cancers such as breast, colon and pancreatic carcinomas, the tumor-associated stroma constitutes the microenvironment necessary to provide their nutritional support and survival/growth factors. In these tissues, cancer-associated fibroblasts express the fibroblast activation protein α (FAP), a dipeptidyl peptidase involved in the proteolytic remodeling of the stromal extracellular matrix of the tumor. Accordingly, high levels of stromal FAP correlate with a rapid progression of colorectal cancers, for example, increasing the potential for the development of metastasis. The presence of FAP on the surface of the cells is associated with other enzymes (specially metalloproteinases) and their regulators in order to promote an extensive degradation of the extracellular matrix. FAP is the only peptidase able to type-I collagen as a substrate and it acts in association with matrix metalloproteinases to produce biologically active fragments of denatured collagen. Therefore, the resulting proteolytic degradation (remodeling) of the extracellular matrix allows the neoplastic cells to invade the surrounding tissues, to migrate to distant sites (metastasis) and the increase in the microvessel density (angiogenesis) to provide the proper nutrition of the tumor. Herein we reviewed the role of FAP in cancers and the main synthetic and computer-aided strategies for the development of FAP inhibitors. As an example of structure-based drug design, we also used docking simulations coupled to in silico analyses of pharmacokinetics and toxicity profiles to identify new potential FAP inhibitors. In this concern, we started from 60,000 structures and applied a shape-fitting sampling algorithm to select compounds that could potentially fit into the binding pocket of FAP. The top 2% compounds were rescored and had their binding affinity energies calculated. We studied the binding modes for the top-twelve compounds, estimating their drug-likeness and predicted some toxicity endpoints. All ligands displayed significant binding affinity energies, and none was potentially mutagenic or tumorigenic and only one was expected to be teratogenic. Nine of the twelve selected compounds displayed drug-likeness scores that would confer a proper lipophilicity balance for oral use. Although these compounds must be subjected to experimental validation concerning FAP inhibition, they seem promising due to the good predicted binding affinities, adequate pharmacokinetic profiles and general low toxicity.