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2,3,9,10-Substituted pentacene tetraesters and pentacene diester-dinitriles were synthesized. These pentacene derivatives underwent an unusual solid state [4 + 4] thermal dimerization with good efficiency and complete stereoselectivity. This observation indicates this series of pentacene derivatives adopt π-π stacking geometry with large mutual overlap in solid state. This notion was confirmed by molecualr dynamic simulation.

Protein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3) is highly expressed in a variety of cancers, where it promotes tumor cell migration and metastasis leading to poor prognosis. Despite its clinical significance, small molecule inhibitors of PRL-3 are lacking. Here, we screened 1443 FDA-approved drugs for their ability to inhibit the activity of the PRL phosphatase family. We identified five specific inhibitors for PRL-3 as well as one selective inhibitor of PRL-2. Additionally, we found nine drugs that broadly and significantly suppressed PRL activity. Two of these broad-spectrum PRL inhibitors, Salirasib and Candesartan, blocked PRL-3-induced migration in human embryonic kidney cells with no impact on cell viability. Both drugs prevented migration of human colorectal cancer cells in a PRL-3 dependent manner and were selective towards PRLs over other phosphatases. In silico modeling revealed that Salirasib binds a putative allosteric site near the WPD loop of PRL-3, while Candesartan binds a potentially novel targetable site adjacent to the CX5R motif. Inhibitor binding at either of these sites is predicted to trap PRL-3 in a closed conformation, preventing substrate binding and inhibiting function.

Due to their active roles in regulating phosphorylations, protein tyrosine phosphatases (PTP) have emerged as attractive targets in diseases characterized by aberrant phosphorylations such as cancers. The activity of the phosphatase of regenerating liver 3, PRL3, has been linked to several oncogenic and metastatic pathways, particularly in breast, ovarian, colorectal, and blood cancers. Development of small molecules that directly target PRL3, however, has been challenging. This is partly due to the lack of structural information on how PRL3 interacts with its inhibitors. Here, computational methods are used to bridge this gap by evaluating the druggability of PRL3. In particular, web-based pocket prediction tools, DoGSite3 and FTMap, were used to identify binding pockets using structures of PRL3 currently available in the Protein Data Bank. Druggability assessment by molecular dynamics simulations with probes was also performed to validate these results and to predict the strength of binding in the identified pockets. While several druggable pockets were identified, those in the closed conformation show more promise given their volume and depth. These two pockets flank the active site loops and roughly correspond to pockets predicted by molecular docking in previous papers. Notably, druggability simulations predict the possibility of low nanomolar affinity inhibitors in these sites implying the potential to identify highly potent small molecule inhibitors for PRL3. Putative pockets identified here can be leveraged for high-throughput virtual screening to further accelerate the drug discovery against PRL3 and development of PRL3-directed therapeutics.

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