G4Redox · ‘Development of hypoxia-activated quadruplex DNA binders as potential cancer therapeutics’

Cancer is the second leading cause of death globally. In spite of the great advances in cancer therapy over the past two decades, there is still a pressing need to develop new therapies with reduced side effects caused by conventional therapies. Historically, many chemotherapeutic approaches to treat cancer, have targeted DNA. But targeting genomic DNA has some disadvantages such as undesired side effects due to low selectivity of most chemotherapeutics (e.g. cisplatin and alkylating agents). In this project I aim to address this problem via the development of ‘smart’ compounds that have the following features: (i) target G-quadruplex DNA structures instead of duplex DNA; this non-canonical DNA topologies form transiently during replication and transcription (as well as in the telomeric region) and have been identified as attractive targets for anticancer drugs (ii) developing compounds that are only activated in tumors and not in healthy tissue to achieve this, I have designed pro-drugs that are only activated in the hypoxic (low levels of oxygen) conditions present in tumors and only when activated can target G-quadruplex DNA (iii) my ‘smart’ compounds will not only target G-quadruplex DNA once activated but will release a second drug able to target other cancer molecular targets (e.g. topoisomerase I, COX-2) to cause a cumulative response of the chemotherapeutic agent. I expect to see significant synergism between the different chemotherapeutics released upon activation of the pro-drug. This synergy in the activities is expected to play an important role to overcome drug resistance. The multidisciplinary nature of the project is strong. The proposal includes both way transfer of knowledge between the host group at Imperial College of London and the candidate in new advanced skill sets and techniques. The proposed work will expand my experience, research competencies, and professional networks, enhancing the development of my career as an independent researcher.