Projektbeschreibung
Multitargeting-Strategie zur Überwindung von Krebstherapieresistenz
Die Entstehung und Entwicklung von Krebs wird von vielen Parametern beeinflusst, unter anderem von der Genetik, der Umwelt und epigenetischen Faktoren. Daher könnten Wirkstoffe, die gleichzeitig auf mehrere epigenetische Enzyme abzielen, eine vielversprechende therapeutische Strategie zur Überwindung von Krebstherapieresistenz sein. Unter dieser Prämisse werden im Rahmen des EU-finanzierten Projekts EpiPolyPharma neue Moleküle entwickelt, die auf die Methylierung und Acetylierung von Proteinen abzielen (die in epigenetischen Prozessen häufig vorkommen). Die Forschenden untersuchen vor allem Enzyme, die in verschiedenen Wegen gleichzeitig zusammenarbeiten, um dem Tumorwachstum entgegenzuwirken. Da die vielversprechendsten Inhibitoren in Zelltests und auf ihre Auswirkungen auf die Regulierung der Transkription von Krebsgenen untersucht werden, sieht das Projekt zusätzliche personalisierte Waffen zur Krebsbekämpfung und der damit verbundenen Arzneimittelresistenz vor.
Ziel
Cancer is a multifactorial disorder involving different genetic and epigenetic alterations. Since epigenetic modifications are brought about by multiple enzymes working synergistically, multitargeting compounds may be particularly effective to acutely interfere with aberrant processes. The simultaneous inhibition of two or more enzymes by a single molecule provides improved therapeutic efficacy compared to single-target inhibitors, along with reduced insurgence of drug resistance.
Through this project, I aim at developing novel therapeutics targeting protein (de)methylation and (de)acetylation for application in cancer therapy. I will synthesise and evaluate hybrid molecules inhibiting two enzymes at the same time. I will develop two classes of compounds targeting the Lysine-specific histone demethylase 1A (LSD1) and either Protein arginine N-methyltransferase 5 (PRMT5) or Histone deacetylases 1-2 (HDAC1-2). These enzymes cooperate in different pathways that lead to cancer insurgence and progression, hence dual targeting represents a successful strategy to counteract tumour growth.
To achieve the outlined aims, I will employ a multidisciplinary approach requiring the fusion of knowledge and tools from medicinal chemistry, biochemistry, biophysics, molecular and cell biology. Through the employment of cutting-edge synthetic approaches, I will prepare LSD1/PRMT5 and LSD1/HDAC1-2 inhibitors which will be assessed through multiple biochemical and biophysical assays. I will also employ native mass spectrometry to investigate their mode of action in the context of the multi-protein complexes formed by the protein targets. The most promising inhibitors will be evaluated in cellular assays to assess their anticancer properties and their effects on transcriptional regulation.
This project will open innovative avenues for personalised therapies and provide additional weapons to overcome drug resistance, along with adding new knowledge on the epigenetic mechanisms of cancer.
Wissenschaftliches Gebiet
- medical and health sciencesbasic medicinemedicinal chemistry
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistance
- medical and health sciencesclinical medicineoncology
- natural sciencesbiological sciencesbiophysics
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
Programm/Programme
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Aufforderung zur Vorschlagseinreichung
Andere Projekte für diesen Aufruf anzeigenFinanzierungsplan
MSCA-PF - MSCA-PFKoordinator
00185 Roma
Italien