Discovered in the early 1900’s, chemotherapy refers to the use of specific medicines to eradicate cancer cells from the body or to delay cancer growth. Chemotherapy remains the backbone of treatment for most patients with cancer and it is often used in combination with other agents.
Although significant progress has been made in the development of novel, targeted small molecules and antibodies, these agents have only been successful in certain indications. Furthermore, even if initially effective, most patients will experience disease progression on targeted agents and will therefore receive chemotherapy at some point during their treatment pathway.
While conventional chemotherapy is central to the treatment of many solid and haematological malignancies and will remain so for the foreseeable future, its efficacy is limited by cancer cell resistance mechanisms and it is often poorly tolerated. Thus, more effective and safer chemotherapeutic agents will always have an important role to play in the treatment of patients with cancer.
Limitations of Existing
Nucleoside analogs are some of the most widely prescribed chemotherapy agents. They block the replication of cancer cells by providing faulty DNA and RNA building blocks during the cell division process, thus leading to cell death, or apoptosis. Some nucleoside analogs exert their effect by blocking enzymes necessary for the production of these DNA and RNA building blocks.
However, there are cancer resistance mechanisms that limit the efficacy of nucleoside analogs. The key resistance mechanisms are:
Insufficient expression of membrane transporters which are required for cellular uptake
Rate-limiting phosphorylation step which is required for activation
Susceptible to breakdown releasing toxic by-products
ProTides - A New Horizon for Chemotherapy
ProTide technology was invented by our late Chief Scientific Officer, Professor Christopher McGuigan at Cardiff University. The unique feature of his discovery was the specific combinations of aryl, ester and amino acid groups (phosphoramidate motifs) that protect the activated nucleotide analog. This phosphoramidate chemistry approach is the key to the ProTide technology.
Every ProTide grouping is distinct, and Professor McGuigan and his team synthesised and tested thousands of compounds in order to identify the optimal phosphoramidate motif for each underlying nucleoside analog.
Professor McGuigan’s work helped lead to the development of several FDA-approved antiviral drugs containing ProTides, including: Gilead's sofosbuvir, (Sovaldi®), and tenofovir alafenamide fumarate (TAF), a ProTide transformation of tenofovir (Viread®). The Sovaldi and TAF franchises were the two most successful drug launches in the history of medicine as measured by their first twelve months revenue post-launch.
Most recently Gilead’s ProTide remdesivir (Veklury®), was approved for the treatment of patients with COVID-19.
ProTides are rationally designed to overcome the limitations of nucleoside analogs. Our researchers have invested over two decades of work in designing, synthesising and screening ProTides designed to overcome the key cancer cell resistance mechanisms and improve the survival outcomes for patients. Having created thousands of ProTides, we have considerable insight in understanding phosphoramidate chemistry and how our selected ProTides are able to exert their anti-cancer effects.
We are applying ProTide technology to nucleoside analogs currently approved as anti-cancer therapies and to novel nucleoside analogs.
NuCana’s ProTides are new chemical entities specifically designed to overcome the key challenges associated with nucleoside analogs:
Enters cancer cells independently of nucleoside transporters
Pre-activated, thus bypassing rate-limiting phosphorylation
Resistant to breakdown by deaminases and dehydrogenases
Harnessing the Power of
ProTides generate much higher levels of the active anti-cancer metabolites inside tumour cells compared to nucleoside analogs, giving ProTides the potential to be more effective than the current standards of care.
ProTides resist breakdown by deaminase and dehydrogenase enzymes that commonly breakdown nucleoside analogs. This makes ProTides more stable improving their pharmacokinetic profile whilst also reducing the generation of toxic by-products that result from the breakdown of nucleoside analogs like gemcitabine and 5-FU. Our most advanced ProTide candidates, Acelarin (NUC-1031) and NUC-3373, are new chemical entities derived from the nucleoside analogs gemcitabine and 5-FU, respectively, two widely used chemotherapy agents. Our lead compound, Acelarin, is in a global Phase III study and our second ProTide, NUC-3373, is in Phase I studies. Our third ProTide NUC-7738, a new chemical entity derived from 3’-deoxyadenosine, is in a Phase I study.
The clinical results we have seen to date have been highly promising and we are extremely encouraged by what has been achieved. This drives us on to expedite the development of these important new agents.