Expanding the Target Space in Oncology: Discovery, Development, and Functional Profiling of Drug-Like Heterocycles

This doctoral research project, entitled “Expanding the Target Space in Oncology: Discovery, Development, and Functional Profiling of Drug-Like Heterocycles,” focused on the development of innovative strategies for anticancer drug discovery through the rational design of heterocyclic compounds with drug-like properties. The project was carried out at the Department of Pharmacy, in a Medicinal Chemistry laboratory under the supervision of Prof. La Motta, where novel compounds were designed, synthesized, and structurally characterized. Part of the research activity was conducted abroad, at Dalhousie University (Canada), under the supervision of Prof. Marcato, in a molecular biology laboratory, where cellular assays and biological validation studies were carried out. The project also benefited from collaborations with multiple research groups, enabling the integration of complementary expertise across chemistry and biology. The overarching objective of the project was to expand the current “target space” in oncology by addressing tumor complexity through the modulation of emerging and underexplored biological targets. In this context, special attention was devoted to the Aldehyde Dehydrogenase 1A (ALDH1A) enzyme family, particularly the ALDH1A3 isoform, as a key driver of cancer stemness and therapy resistance. Overall, this research project provided novel chemical tools and integrated therapeutic strategies to address tumor heterogeneity and resistance, highlighting the value of combining multiple targeting approaches within a unified framework for next-generation anticancer drug development.