Discovery and development of small molecules, prodrugs and PROTACs: the role of a modular and reliable chemistry

Drug discovery is an ever-evolving process, driven by the identification of potential disease targets and the emergence of novel technologies and synthetic strategies. In this context, my doctoral research encompasses the development of small molecules (prodrugs and dual targeting inhibitors) and protein degraders (PROTACs) as therapeutic approaches for different diseases, including ultra-rare genetic diseases, autoimmunity, and cancer. To access these compounds, I explored various synthetic methodologies, including multicomponent reactions (MCRs), click chemistry, and electrochemistry. The use of MCRs has enabled to expand the chemical toolbox thanks to the discovery of a new variant of the Ugi reaction, based on the use of tritylamine as a substitute for ammonia. This allows for the different functionalization of compounds, leading to the synthesis of diamide derivatives as precursors for 5- sulfamido oxazoles. This reaction, combined with other MCRs were employed for the setup of a platform for the rapid synthesis of PROTACs, minimizing development times and broadening the applicability of this strategy to various targets. Then, this platform was exploited in the synthesis of PROTACs targeting BRD4 and a degrader active at the low nanomolar level was found. Besides BRD4, most efforts have been directed towards Store-Operated Calcium Entry (SOCE) and dihydroorotate dehydrogenase (DHODH), that were both targeted individually and synergistically. In the context of SOCE, the previously reported CIC-39 effective in vivo in ultra-rare conditions such as TAM, has been investigated to facilitate early-stage administration in diseases treatment, developing prodrugs as long-term delivery depot injections. Additionally, the combined targeting approach for SOCE and DHODH has been explored as an advantageous strategy for counteracting autoimmune diseases and has led to the discovery of a balanced dual inhibitor.