**3. Targeted drugs for PDE6δ inhibition**

Post-translational modifications are important for the recognition and transport of KRas4B to the plasma membrane; therefore, the study of molecules responsible for recognizing these post-translational modifications may be an important therapeutic target against PDAC [26]. One of the proteins responsible for recognizing the post-translational modification is phosphodiesterase 6δ (PDE6δ), which recognizes the farnesylation or geranyl-geranylation present in the cysteine of the CAAX motif of Kras4B protein [27]. A group of German researchers identified and evaluated the compound called Deltarasin, which interacts with PDE6δ, with a Kd of 38 nM, prevents the recognition of the post-translational modification present in KRas4B, arresting KRas4B in the cytosol, and consequently preventing its activation and tumor progression. This compound was named the first generation of PDE6δ inhibitors [26]. However, its evaluation in noncancerous pancreatic duct cell lines showed high cytotoxicity; this affected considerably the cell viability at low concentrations [28]. In 2016, the analogue of the compound Deltarasin (second generation of PDE6δ inhibitors) was reported, and it was called deltazinone. This analogue presented constant dissociation of Kd 38 nM to Kd 4 nM, thus showing to be a compound with better interaction energy than the analogue of first generation. Deltazinone showed cytotoxic effects on pancreatic cancer cell lines at a concentration of 24 μM, but it took about 8 h to have an anti-proliferative effect on pancreatic cancer cell lines. Conversely, Deltarasin, at a concentration of 5 μM showed the same effect in 1 hour. Considering these data, the first generation of PDE6δ inhibitors have a better performance than the ones from the second generation [29, 30]. In 2017, the third generation of specific PDE6δ inhibitors, which were called Deltasonamides, was reported. This new generation shows more interaction energy than the ones from the first generation and greater cytotoxic effects on pancreatic cancer cell lines at concentrations from 1 to 12 μM [31].

In early 2019, drugs based on triazoles arose. These compounds can be considered as the fourth generation of PDE6δ inhibitors since they used the structure of Deltarasin to be able to find the functional group with the highest interaction energy with PDE6δ. This fourth generation is still in *in vitro* studies in order to evaluate its cytotoxic effect [32]. At the beginning of 2020, the fifth generation of PDE6δ inhibitors, called Deltaflexin, arose; although they are analogues of Deltarasin, they do not have the same cytotoxic effects showed by the first generation of PDE6δ inhibitors [33].
