Ferroptosis Inhibitors For Neurodegenerative Disorders

Project Information

NeuroFerro

Grant agreement ID: 101065370

DOI

10.3030/101065370

Project closed

EC signature date 12 August 2022

Start date 1 October 2022

End date 31 March 2025

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 239 700,00

Coordinated by

UNIVERSITEIT ANTWERPEN
Belgium

Periodic Reporting for period 1 - NeuroFerro (Ferroptosis Inhibitors For Neurodegenerative Disorders)

Reporting period: 2022-10-01 to 2025-03-31

Summary of the context and overall objectives of the project

Neurodegenerative diseases represent a growing healthcare burden worldwide, yet there are no available cures. Recent studies have identified ferroptosis, a form of regulated cell death associated with iron and lipid peroxidation, as a significant contributor to neurodegeneration. However, effective therapeutic strategies targeting ferroptosis are lacking, especially those capable of crossing the blood-brain barrier (BBB). The NeuroFerro project aimed to address this unmet need by developing novel ferroptosis inhibitors with optimized properties for central nervous system (CNS) targeting. The primary objective was to create radical-trapping antioxidants (RTAs) with improved oral bioavailability and BBB permeability. These compounds were intended to serve both as research tools to study the role of ferroptosis in neurodegeneration and as lead candidates for drug development. Through a comprehensive research and development strategy combining medicinal chemistry, in vitro and in vivo biological evaluations, and physicochemical profiling, the project has significantly expanded the available toolbox for ferroptosis research. The outcomes contribute to Europe's efforts to advance health innovation, promote healthy ageing, and position the EU as a leader in biomedical sciences.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The project successfully synthesised 54 novel ferroptosis inhibitors, including 38 phenothiazine and 16 ferrostatin derivatives. These compounds were designed based on the structure–activity relationship (SAR) knowledge developed over years of research by the group of Prof. Koen Augustyns (project supervisor) and on calculated CNS Multiparameter Optimization (MPO) scores—a computational tool used to predict BBB permeability, particularly at early stages of drug discovery projects. Comprehensive biological evaluations were conducted, including radical-trapping activity assessments (FENIX assay), in vitro anti-ferroptotic potency evaluations, metabolic stability tests, and permeability studies. Nine compounds were prioritised based on their profiles, and three lead candidates were selected for in vivo pharmacokinetic studies. In vivo experiments confirmed that the selected compounds achieved measurable concentrations in brain tissue. One of the compounds was also tested for its presence in cerebrospinal fluid, further validating its BBB permeability. Intellectual property protection was secured through the patent application WO2024062043. In addition to the scientific work, the project involved significant professional development activities, including workshops on project management, grant writing, and science communication, all of which contributed to the researcher’s leadership skills and career progression.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

NeuroFerro delivered a new class of BBB-penetrant ferroptosis inhibitors with nanomolar potency, high radical-trapping efficiency, and favourable pharmacokinetic properties. Compared to existing ferroptosis inhibitors, the project's compounds offer superior CNS-targeting capabilities, addressing a critical limitation in the field.
The project also introduced a rational approach to optimising CNS drug-likeness by combining predictive computational tools with extensive experimental validation. The results provide a strong foundation for further preclinical development and clinical translation. The selected compounds can serve as tool compounds to further study the relevance of ferroptosis in neurodegenerative diseases, and the molecules themselves can be used for further optimisation during the hit-to-lead stage of drug discovery. Future efforts should focus on in vivo efficacy studies in disease models and securing access to future financing and commercialisation support.