CIBSS - Centre for integrative Biological Signalling StudiesCIBSS

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Small molecule discovery for metabolic signalling research: from immunomodulators to cancer therapeutics

Prof. Dr. Olaf Groß (CIBSS-PI), Institute of Neuropathology, (University Medical Center, Faculty of Medicine)

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The integration of cellular metabolism with signal transduction provides means to align cell fate and function with environmental cues. The inflammasome drives pathogenic inflammation in numerous diseases, and recent evidence suggests mitochondrial and metabolic signals are common triggers of inflammasome activity. We discovered that imiquimod, a topical immune-stimulatory anti-cancer drug, inhibits mitochondrial respiratory chain complex I, leading to inflammasome activation through production of oxygen radicals. Complex I inhibitors suppresses cancer cell proliferation by blocking mitochondrial NAD+ regeneration that is required for anabolic growth. Direct metabolic and anti-cancer effects have also been reported for the widely-used anti-diabetic drug metformin, suggesting that modulation of metabolism may represent an underappreciated factor in drug efficacy.

In this project, together with industry, we screen small molecule drugs for the ability to modulate metabolism and to trigger inflammasome activity. The identified compounds will be used as tools to study and control these processes.