Abstract

The search for new therapeutic strategies represents one of the main challenges in the field of oncology, particularly in combating tumour progression, metastasis and drug resistance. In this context, the deubiquitinase protein USP7 (Ubiquitin-Specific Protease 7) has emerged as a promising molecular target, thanks to its role in regulating the stability and function of numerous proteins involved in cell proliferation, the response to DNA damage, apoptosis and the immune response. 

Despite growing interest, no drugs targeting USP7 have yet been approved for clinical use. In this context, the compound STIRUR-41 has been identified as a promising pyrazolone-based inhibitor of USP7. This project involves the rational design of a new library of pyrazolone derivatives identified using virtual screening and molecular docking techniques. The most promising compounds will subsequently be synthesised, giving priority, where possible, to environmentally sustainable synthesis methods in accordance with the principles of Green Chemistry. The new molecules will then be evaluated using enzymatic assays and innovative proteomic strategies, with the aim of determining their efficacy against USP7 and identifying their mode of interaction with the target.

The lead candidates will finally be studied in tumour cell models to assess their antiproliferative activity, their effect on intracellular USP7 levels and their potential anti-angiogenic properties. The main ADME-Tox characteristics will also be analysed in order to identify the molecules with the best pharmacological profile.

The project could therefore represent a first step towards innovative therapeutic strategies for the treatment of cancer and, in the long term, towards overcoming certain mechanisms of resistance to currently available therapies.