Project description DEENESFRITPL Multitargeting strategy to overcome cancer therapy resistance Cancer onset and development is affected by many parameters, including genetics, the environment, and epigenetic factors. As such, compounds that simultaneously target multiple epigenetic enzymes may be a promising therapeutic strategy to overcome cancer therapy resistance. Using this premise, the EU-funded EpiPolyPharma project is developing novel molecules to target protein methylation and acetylation (common in epigenetic pathways). In particular, the researchers are investigating enzymes that cooperate in different pathways simultaneously to counteract tumour growth. As the most promising inhibitors will be assessed in cell assays and for their effects on the regulation of cancer gene transcription, the project foresees additional personalised weapons to combat cancer and related drug resistance. Show the project objective Hide the project objective Objective 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. Fields of science medical and health sciencesbasic medicinemedicinal chemistrymedical and health sciencesbasic medicinepharmacology and pharmacydrug resistancemedical and health sciencesclinical medicineoncologynatural sciencesbiological sciencesbiophysicsnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Programme(s) HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme Topic(s) HORIZON-MSCA-2021-PF-01-01 - MSCA Postdoctoral Fellowships 2021 Call for proposal HORIZON-MSCA-2021-PF-01 See other projects for this call Funding Scheme MSCA-PF - MSCA-PF Coordinator UNIVERSITA DEGLI STUDI DI ROMA LA SAPIENZA Net EU contribution € 172 750,08 Address Piazzale aldo moro 5 00185 Roma Italy See on map Region Centro (IT) Lazio Roma Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00 Partners (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all UNIVERSITA DEGLI STUDI DI PAVIA Italy Net EU contribution € 0,00 Address Strada nuova 65 27100 Pavia See on map Region Nord-Ovest Lombardia Pavia Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
