‘Development of hypoxia-activated quadruplex DNA binders as potential cancer therapeutics’

Project Information

G4Redox

Grant agreement ID: 101027220

DOI

10.3030/101027220

Project closed

EC signature date 27 April 2021

Start date 4 October 2021

End date 2 January 2024

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 224 933,76

EU contribution

€ 224 933,76

Coordinated by

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
United Kingdom

Periodic Reporting for period 1 - G4Redox (‘Development of hypoxia-activated quadruplex DNA binders as potential cancer therapeutics’)

Reporting period: 2021-10-04 to 2023-10-03

Summary of the context and overall objectives of the project

Cancer is a major health concern and second leading cause of death worldwide. While significant progress has been made in treating cancer over the past few decades, there's still a critical need for better therapies that minimize side effects. Traditional cancer treatments target the DNA of cancer cells which often harms healthy cells too, leading to unwanted side effects. To address this challenge, ‘G4Redox’ focuses on developing "smart" compounds specifically targeting a unique structure in DNA called G-quadruplexes (G4), which are found in cancer cells during their growth process. Unlike normal DNA, these structures are more common in cancer cells. These compounds only become active in the hypoxic (having low oxygen) environments found in tumors, sparing healthy tissues. Once activated, these compounds not only attack the cancer cells by targeting their unique DNA structures but also release additional drugs that target other specific molecular targets that plays crucial role in cancer progression. This combination approach aims to create a more effective treatment, potentially overcoming the problem of cancer cells becoming resistant to one single drugs. This research is crucial for society because it aims to address the pressing need for more effective and targeted cancer therapies. By developing compounds that specifically target G4 DNA in tumor environments, the project seeks to minimize harm to healthy tissues while maximizing the efficacy of treatment. The overall objectives of the project include:
• Designing hypoxia and redox-activated compounds capable of selectively binding to G4 DNA structures in cancer cells.
• Evaluating the affinities towards different forms of DNA structures and topologies.
• Evaluating the efficacy and specificity of these compounds against different forms of cancer to assess their potential as anticancer agents. Investigating the mechanisms underlying the activation and targeting of G4 DNA by the designed compounds.
• Assessing the synergistic effects of combining G-quadruplex-targeting compounds with other cancer therapeutics to enhance treatment outcomes.
In conclusion, this project aims to contribute to the development of novel cancer therapies that are more effective and less toxic. By harnessing the unique properties of G4 DNA and utilizing hypoxia and redox activation mechanisms, the research endeavors to advance the field of cancer treatment.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

From the inception of the project to the current period covered by the report, significant progress has been made in the development of hypoxia and redox-activated G4 DNA targeting platinum prodrugs. The following summarizes the key activities and main results achieved:
1. Compound Design and Synthesis: Extensive efforts have been dedicated to designing and synthesizing novel platinum-based metal complexes capable of selectively binding to G4 DNA structures. Through rational design strategies, several lead compounds have been synthesized and characterized to study the binding affinity and specificity to duplex and quadruplex DNA structures.
2. Activation Mechanisms: Detailed studies have been conducted to elucidate the activation mechanisms of the prodrugs in presence of reducing environments typically found in tumor microenvironments. The results have provided insights into the structural and electronic properties along with modifications necessary for effective activation in tumor environments.
3. Evaluating the affinities towards different forms of DNA structures (duplex and G4 DNAs) and quadruplex topologies. The DNA binding studies with quadruplex sequences having different topologies revealed that PtIV prodrugs having no affinity towards various forms of DNA structures whiles upon cellular activation via reduction, its active counterpart PtII shown excellent binding towards G4s and no affinity towards genomic duplex DNA.
4. In vitro Evaluation: The efficacy and specificity of the synthesized compounds have been evaluated through extensive in vitro studies using cancer cell lines and relevant cellular models. Moreover, detailed studies regarding in vitro cytotoxicity in hypoxic and normoxic condition in different cancer cells, cellular uptake and investigation of mechanism of action have been planned.
5. Exploitation and Dissemination: The results obtained from this project is being prepared as a manuscript titled as “Activation of Pt(IV) complexes under hypoxic conditions yielding Pt(II) complexes with high affinity for G4 DNA” and will be communicated soon. Another paper originated, have been disseminated through a peer-reviewed journal as Reyes, J. B., Sherin, P. S., Sarkar, A., Kuimova, M. K., & Vilar, R. (2023). Platinum(II)-Based Optical Probes for Imaging Quadruplex DNA Structures via Phosphorescence Lifetime Imaging Microscopy. Angewandte Chemie International Edition, 62(42), e202310402.
In conclusion, the project work has significantly advanced our understanding of hypoxia and redox-activated triggered platinum-based G4 binding agents as potential anticancer therapeutics. The main results achieved underscore the feasibility of this innovative approach for targeted cancer treatment. Moving forward, further optimization and validation of the lead compounds will be pursued towards clinical translation, focusing on maximizing therapeutic efficacy and minimizing off-target effects.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The project aims to achieve several breakthroughs:
1. Selective Targeting: The development of compounds that selectively target G4 DNA structures in hypoxic tumor microenvironment expected to enhance the efficacy of treatment while minimizing off-target effects on healthy tissues.
2. Activation Mechanisms: The project aims to increase our understanding of tumor microenvironments and their role in cancer progression. This knowledge may uncover new therapeutic targets and inform the development of personalized treatment strategies for cancer patients.
3. Synergistic Effects: The project seeks to explore the synergistic effects of combining hypoxia and redox-triggered G4 targeting moieties with bioactive compounds. By targeting multiple molecular pathways involved in cancer progression, this combinatorial approach has the potential to overcome drug resistance.
Potential Impacts:
The project outcome is expected to have far-reaching socio-economic implications:
1. Improved Cancer Treatment: The development of novel hypoxia and redox-activated G4 DNA binding agents has the potential to revolutionize cancer treatment by offering more effective and targeted therapies with reduced side effects.
2. Healthcare Cost Reduction: By minimizing the adverse effects associated with conventional chemotherapy and improving treatment outcomes, the project may lead to cost savings in healthcare by reducing hospitalizations and supportive cost.
3. Quality of Life: The availability of more efficacious and tolerable cancer therapies will contribute to improving the quality of life for patients and their families.
4. Scientific Advancement: The insights gained will pave the way for further advancements in cancer research and therapeutic development, inspiring new avenues of innovation in the field.
In summary, the project “Development of hypoxia-activated quadruplex DNA binders as potential cancer therapeutics” holds great promise for transforming cancer treatment and addressing unmet medical needs, ultimately benefiting patients, healthcare systems, and society as a whole.

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