Innovative approaches to cancer therapy

Cancer is a term used to describe complex diseases characterized by abnormal cell-proliferation with different factors to take into consideration, reason for which nowadays there are many types of treatments with limited success. Therefore, innovative anticancer agents are required. Recently, anticancer research has been focused on epigenetics. Among epigenetic actors, Chromodomain (ChD)-containing proteins have gained ever-increased interest. These proteins, whose altered expression or mutations in cancer lead to abnormal gene transcription, are involved in epigenetic regulation of transcription by recognizing methylated lysine residues on histones. According to this information, in the first part of this thesis, an innovative epigenetic approach was applied to design and synthetize small-molecules as potential ChDs binders for cancer treatment. In detail, we reported the identification of two hit compounds (2 and 3) and the further structure-activity relationship studies. A fluorescence polarization competition assay was employed to evaluate the obtained derivatives. Cancer research activities have also taken advantage of innovation in emerging technologies. As an example, technical advances have allowed to apply X-ray crystallography in a high-throughput way for compound screening. Therefore, in the second part of this work a fragment-based drug discovery approach based on high-throughput X-ray crystallography was applied, in collaboration with Paul Scherrer Institute, for identifying new binders of tubulin. In this context, compound 29 was identified as a binder of tubulin Colchicine-site, previously validated for cancer treatment. Structural similarity of this compound with Nocodazole, an antineoplastic agent co-crystallized with tubulin at the same Colchicine-site, and the capability of both molecules to bind the same tubulin pocket, encouraged us to develop two series of 29 analogs by combining synthetic efforts with computer-aided drug design protocols. For some synthetized derivatives, X-ray crystallography and Resazurin assay were employed to evaluate the binding ability at the tubulin Colchicine-site and the capacity to affect cell viability, respectively.