Abstract

Prenylcysteine oxidase 1 (PCYOX1) recently emerged as a promising candidate target for cardiovascular and metabolic disorders. A few evidences show that PCYOX1 can be found associated with plasma lipoproteins (mainly pro-atherogenic VLDL and LDL), and that its pro-oxidant activity is involved in the generation of reactive oxygen species which play a pivotal role in the development of atherosclerotic plaques. The aim of our project is to validate the druggability of PCYOX1 and identify potential hit compounds for future development of cardiovascular and anticancer drugs. In detail, starting from available models of the protein, the Molecular Informatics group of Ri.MED Foundation prepared an in-silico model that will guide structure-based virtual screening campaigns to identify new potential hits and rationalize their binding mode. In parallel, the Medicinal Chemistry group is working on the design and synthesis of a small library of close analogues of the only two known ligands for PCYOX1 (i.e. farnesyl-N-tranylcypromine and farnesyl-S-propargyl). This first set of compounds will help to validate the robustness and sensitivity of the biochemical and cellular assays developed by the partners for the evaluation of both the cardiovascular and cancer biological activity. Furthermore, medicinal chemistry and computational studies will guide the hit structural optimization and family expansion of retrieved primary hits, posing the basis for future developments.

Impact

Cardiovascular diseases and cancer are among the leading causes of death worldwide. There is strong evidence of an association between dyslipidemia, metabolic syndrome, atherosclerosis, and high incidence and aggressiveness in tumor growth. In a highly competitive context, this project aims at clarifying the molecular mechanisms of the protein in atherosclerosis and cancer to advance the prevention and treatment of PCYOX1-driven diseases. Within the partnership with European Institute of Oncology, Centro Cardiologico Monzino and ISMETT (PNRR-POC-2023-12377609), Ri.MED Medicinal Chemistry and Molecular Informatics groups will help to identify new potential modulators of the protein, which will pose the basis for future drug development in cardiovascular and cancer areas.

Our research will provide important insights to further advance our understanding of the protein function and identify pharmacological approaches able to tackle PCYOX1, providing chemical tools to unravel PCYOX1 functions.

Pipeline