For example, while compound 5 is highly FAP selective, the analogue 6 is highly POP selective. This D-Ala-induced selectivity for FAP has been further observed recently. Nevertheless, Christiansen et al. suggested that targeting both FAP and POP blocks stromal invasion and angiogenesis, respectively, and may alter cancer growth. They designed a pseudopeptide dual inhibitor which was found to block tumor growth in mice. These findings suggest that dual inhibition is a promising strategy, though this large, non-drug-like molecule was unsuitable for further consideration. Consequently, although an overview of the literature suggests that selectivity may be easier to achieve than dual inhibition, the latter may be an ideal strategy for designing and developing anti-cancer therapeutics. Selected known POP and FAP inhibitors and their selectivity profiles In 2009, our own group reported a series of [3.3.0] bicyclic POP inhibitors based on compound 2 which were found to be cell-permeant and potent in the sub-micromolar range. This series of nitrile-containing compounds were designed to act as covalent inhibitors targeting the catalytic serine in the POP active site. Interestingly, a few years later, KYP-2047 was co-crystallized with POP, demonstrating the covalent nature of the binding of nitrile derivatives in the active site of POP. However, the series of inhibitors based on compound 2 was halted after metabolism studies revealed it to be metabolized into complex mixtures via oxidation of the sulfur. A few years later, compound 3 was discovered via virtual screening and docking-guided optimization, This inhibitor exhibited a POP inhibitory activity five times more potent than that of our first hit 2 and was active in low-micromolar concentrations on human glioblastoma and endothelial cancer cells. In addition, we found that the introduction of the [4.3.0] bicyclic molecular scaffold improved the metabolic stability of our inhibitors. Five years ago, we also reported the structure-based design and synthesis of a novel class of POP inhibitors based on a hexahydroisoindole scaffold, such as 4 (Figure ). A docking study guided the selection of structures (both in terms of stereo-and regiochemistry) for synthesis.