Design of SF3B1 subunit modulators of the SF3B spliceosome complex

Abstract

The subject of this dissertation is the search for new therapeutic strategies for pancreatic cancer and aims to implement a Drug Discovery process for the rational design and synthesis of molecules active in the modulation of pathways related to the regulation of pre-mRNA splicing process. This research project is the result of a joint PhD between the University of Palermo, Italy, and the Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands. It integrates complementary skills in pharmaceutical chemistry and translational cancer research with a special focus on the rational design of new anticancer compounds potentially active on SF3B1 (Splicing Factor 3B subunit 1), an effective therapeutic target involved in the pre-mRNA splicing process. Furthermore, SF3B1 is a frequently mutated gene in haematological malignancies and some solid tumors, including pancreatic cancer. Specifically, pancreatic ductal adenocarcinoma (PDAC) is the most common type of exocrine pancreatic cancer with a highly poor prognosis and an increasing incidence. The urgent need to find effective therapeutic strategies for the treatment of this disease prompted us to evaluate the antitumor activity of these compounds on preclinical models of PDAC. Based on the interesting anticancer properties described for the imidazothiadiazole nucleus as a scaffold for the development of pharmacologically active derivatives, we were encouraged to continue with the same approach. A preliminary computational study led us to the realization of a common pharmacophore that was used for the virtual screening of an in-house molecular library and commercially available molecular libraries, in order to identify the molecular scaffold of interest and then select the most promising molecules that were tested in vitro on PDAC cell lines. We also tested for the first time two splicing modulators targeting SF3B1, in order to identify new potential therapeutic targets for the treatment of PDAC. Furthermore, the status of the transmembrane protein hENT-1 (human Equilibrative Nucleoside Transporter-1) as a potential biomarker in PDAC is explored in detail in the present Thesis. In conclusion, the need to find new diagnostic biomarkers and the interesting antiproliferative activity previously shown by imidazothiadiazole compounds prompted us to extend the evaluation of the biological activity in vitro concerning a new class of imidazothiadiazole compounds