Development of dual-targeting epigenetic modulators for polypharmacology-based cancer therapy

Projektinformationen

EpiPolyPharma

ID Finanzhilfevereinbarung: 101062363

DOI

10.3030/101062363

Projekt abgeschlossen

EK-Unterschriftsdatum 16 Juni 2022

Startdatum 1 Oktober 2022

Enddatum 30 September 2024

Finanziert unter

• Marie Skłodowska-Curie Actions (MSCA)

Gesamtkosten

Keine Daten

EU-Beitrag

€ 183 970,08

Koordiniert durch

UNIVERSITA DEGLI STUDI DI ROMA LA SAPIENZA
Italy

Periodic Reporting for period 1 - EpiPolyPharma (Development of dual-targeting epigenetic modulators for polypharmacology-based cancer therapy)

Berichtszeitraum: 2022-10-01 bis 2024-09-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

Scientific objectives.
The specific scientific objectives of the MSCA-PF EpiPolyPharma described in Annex 1 are outlined below.
Objective 1: To identify first-in-class dual LSD1/PRMT5 inhibitors and to characterise their biochemical and biological properties.
Progress: Significant advancements have been made, including the synthesis of new compounds, and comprehensive biochemical and cellular assays were conducted. The work included enzyme activity testing, cellular viability assays, and target engagement analysis in AML cell lines. X-ray crystallography confirmed the binding mode of one key inhibitor.
Achievement Status: Almost fully achieved.

Objective 2: To identify novel highly potent and selective dual LSD1/HDAC1-2 inhibitors and to assess their biochemical and biological properties.
Progress: Novel hybrid compounds were designed and synthesized, followed by enzymatic and cellular evaluations. The most promising compounds demonstrated selective inhibition of LSD1 and HDAC1/2 and were validated in various cancer cell lines for their antiproliferative activities and their effect on key cellular biomarkers was evaluated.
Achievement Status: Almost fully achieved.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Results Beyond the State of the Art
The MSCA-PF EpiPolyPharma project has made significant advancements in the field of targeted cancer therapy by developing first-in-class dual inhibitors for LSD1/PRMT5 and novel dual LSD1/HDAC1-2 inhibitors. These dual inhibitors were shown to effectively modulate biological pathways involved in cancer cell viability and apoptosis, demonstrating their potential as polypharmacological agents.
• Key Achievements:
o Development of Novel Compounds: The project successfully synthesized and evaluated multiple novel dual-target inhibitors that exhibited potent inhibition in biochemical assays and demonstrated selective activity in cell-based models.
o Mechanistic Insights: Structural analysis via X-ray crystallography provided detailed binding modes of the compounds, confirming interactions with target proteins. This contributed to the understanding of how these dual inhibitors engage their targets.
o Biological Validation: The dual inhibitors proved more effective than single-target treatments in reducing cell viability and inducing apoptosis in various cancer cell lines. Compounds like 1a and 21c showed higher efficacy than reference compounds in inducing DNA damage and promoting cell death.

Potential Impacts and Future Needs
• Scientific and Societal Impact:
o The project has contributed to advancing dual-targeted approaches in cancer therapy, offering a new paradigm that could lead to more effective treatments with potentially fewer side effects than traditional chemotherapy.
o The results lay a foundation for future development of more refined dual inhibitors with improved potency and selectivity.
o These inhibitors serve as valuable chemical tools that can be utilized in further research to explore broader implications in cancer biology and treatment strategies.
• Needs for Further Uptake and Success:
o Further Research and Demonstration: Continued optimization of these compounds and investigation of pharmacokinetic and pharmacodynamic profiles is required for transitioning from chemical tools to preclinical candidates.
o Preclinical and Clinical Testing: Comprehensive in vivo studies and eventual clinical trials are needed to establish the safety, efficacy, and therapeutic potential of these compounds.

Conclusion
The MSCA-PF EpiPolyPharma project has not only demonstrated the feasibility of developing dual-target inhibitors but also showcased their potential to modulate critical pathways in cancer cells more effectively than traditional single-target approaches. While substantial progress has been made, further research, strategic collaborations, and funding will be essential to advance these promising compounds to clinical use and maximize their impact on cancer treatment.