Imaging cellular stress responses to discover protective medicines
The IM4DD project brought together academic and industrial partners, including Specs and Sciex, to successfully develop a roadmap for developing an innovative platform combining high-resolution microscopy and live single-cell metabolomics. The partnership with Specs enabled the design and generation of a 1500 compounds library targeting specifically the Nrf2 pathway. Using advanced cell imaging of fluorescent reporters we were able to identify novel compounds that activate the oxidative stress response. The partnership with Sciex enabled the development and testing of the key building blocks for establishing an automated single cell autosampler into segmented flow for nanospray mass spectrometry analysis. The collaboration strengthened Dutch life sciences and built a foundation for drug discovery targeting diseases such as Parkinson’s, Alzheimer’s, and organ damage.
Chronic diseases involving oxidative stress are responsible for over 70% of global deaths, highlighting a pressing need for better therapies. Traditional drug discovery often overlooks complex cellular behaviours, making innovation essential to improve patient health outcomes and reduce societal healthcare burdens. The IM4DD project addressed this by integrating advanced cell biology, imaging, and metabolomics techniques to uncover protective mechanisms in human cells.
The project integrated fluorescent reporter cell lines with mass spectrometry, providing quantitative imaging. By collaborating with Specs, a focused compound library of over 1500 molecules was screened to identify lead compounds modulating the Nrf2 antioxidant response pathway. The approach offers insight into cellular heterogeneity and disease-relevant biology, enabling translation to patient-derived models and therapeutic development.
Results showed the establishment of a drug discovery platform capable of assessing molecular activation of the Nrf2 pathway with high specificity. Several novel lead compounds were identified and validated across multiple image-based assays using SRXN1 and Nrf2 reporter lines. The lead compounds were protective against oxidative stress-induced cytotoxicity. Follow-up metabolomics studies are planned to map effects on core metabolic pathways, with carefully defined time points and compound concentrations. These findings pave the way for innovative therapies aimed at enhancing cellular resilience to oxidative stress. Although, substantial advances have been made for the full integration of single-cell sampling. The IM4DD project has laid the groundwork for translation into patient-derived models and future drug development.
