Design and Synthesis of Novel Chemical Entities with Anticancer Activity

Currently, the canonical approach for the treatment of most of the malignancies is based on kinase inhibitors, in particular Tyrosine-Kinase Inhibitors (TKIs). Despite the great results obtained with the introduction in clinic of the first TKIs (e.g. Imatinib), the scientific community had to face soon with the limitations that these molecules bring with them. They present severe adverse effects, for their reduced selectivity between healthy and tumor cells. Furthermore, these drugs are prone to lead to the onset of resistances in patients. This last aspect causes the failing of the therapy and the recrudescence of the pathology. For these reasons, with the aim to explore other therapeutic options, that do not present the same limitations previously mentioned, this work has been focused on the development of new classes of anticancer molecules. For doing this, new molecular scaffolds have been synthetized, having as therapeutic targets enzymes that do not include Tyrosine Kinases. This research has led to the development of three different lines of research. The first project has been focused on the synthesis of new activators of a well-known oncosuppressor: the serine/threonine phosphatase PP2A. An important part of this project has been based also on the study of the pharmacokinetic profile of these new molecules in animal models and the development of new fluorescent tools useful for the detection of the enzymatic activity of the desired phosphatase and the determination of the effective mechanism of action of the new synthetized compounds in whole cell lysates. The second research branch has been based on the development of new molecules that are able to reactivate another important oncosuppressor, that is present in the downstream cascade of PP2A, the tyrosine phosphatase SHP-1. Both these new approaches present several advantages and innovations if compared with the classical TKIs. Indeed, in several kind of malignancies, PP2A and SHP-1 are strongly downregulated and the possibility to repristinate a physiological level of their activity in the tumor cells can induce apoptosis in cancerous cells without affecting the healthy ones. This is possible because in the normal cells the activity of these phosphatases is already at a basal level and for this reason these cells are not affected by the new molecules, granting a certain degree of selectivity between tumour and healthy cells. Furthermore, this approach seemed to be extremely promising also for avoiding the onset of resistances. This due to the fact that this pharmacological approach is effective also on tumor stem cells, that are usually insensitive to the classical treatments. The third research line has been focused on the development of new molecules able to inhibit a serine/threonine kinase: CK2. CK2 is overexpressed in almost all known malignancies. It plays a crucial role in the control of the cell fate and in the mechanisms of resistances to the drug induced apoptosis. The development of new CK2 inhibitors is gaining interest in the last decade. This is due to the fact that this enzyme is a valid therapeutic option because it is the downstream effector of all the 2 principal oncogenic pathways present within the cell. Counteracting the overexpression of this kinase is not only promising for its therapeutic efficacy but also for the intrinsic reduced risk of inducing the onset of resistances.