PhoreMost Receive Innovate UK Funding
Blog May 21, 2015
Despite massive advances in the treatment of cancer there are still many forms which are almost completely undruggable. One company who aims to change this, Phoremost, have recently received funding from Innovate UK. Primarily this investment will support their flagship project, aimed at developing a drug for cancers caused by the untreatable KRAS gene mutation.
JR: You have recently received a significant funding boost. Can you give me some details about why Innovate UK selected PhoreMost?
Chris Torrance (CT): Innovate UK aims to have a maximum impact on the UK public and the UK economy. Firstly, projects are selected that can have a substantial effect on a current public health problem (in our technology sector). Secondly, Innovate UK selects the companies behind the chosen projects that have the potential to benefit the sector in the long-term, further growing and diversifying an innovative UK economy. PhoreMost, with its first-in-class lead drug discovery programme, is addressing an initial unmet healthcare need in the form of a highly lethal form of cancer driven by a defective gene called ‘KRAS’. In the longer-term, PhoreMost is also developing a new technology that can systematically translate advances in our understanding of genetics into many other targeted therapies for unmet diseases, and is dedicated to bringing those to market at lower costs to the patient. These factors together, if we are successful, could stimulate a revolution in drug discovery and a sustainable model for modern personalised medicine, which I believe led to us being selected for this award.
JR: Could you tell me more about PhoreMost’s protein interference technology and how this led to the development of the Site-Seeker screening platform?
CT: Protein-interference technology (Protein-i) lies at the heart of the Site-Seeker platform and will address the growing list of disease targets currently considered ‘undruggable’ by the pharmaceutical industry. ‘Site-Seeker’, in its totality, is the use of Protein-i to first find new 3D-target sites associated with a disease and then rapidly convert this 3D-spatial information into novel chemical matter that can then be rapidly developed by pharmaceutical companies into new drug. Protein-i is a novel drug target screening and validation technology that can systematically unmask hidden, or ‘cryptic’, drug sites across the entire human genome and then link them directly to a useful therapeutic function in a live-cell context. It does this by screening a vast array of 3-dimentional ‘shapes’, which are encoded by a library of small, self-folding, protein fragments, for their ability to reverse a disease cells behaviour. These shapes bind to a complementary drug-like site in a target protein, which once defined, provides chemists with the critical 3D spatial information they need to rationally design new small-molecule therapeutic agents.
JR: One of your key aims is to develop a treatment for tumours caused by mutations in the KRAS gene. Why has this not been possible before?
CT: Nobody has previously been able to find key druggable sites on mutant KRAS itself. Even today, many proponents of trying to tackle this common, yet stubborn cancer gene, still consider this to be true and have therefore tried to address it less direct ways, either preventing its correct localisation in a cell or by drugging downstream effectors believed to be important. These approaches have failed, however, largely due to the biology of cells being highly malleable by having a lot of in-built pathway redundancy. This is commonly exploited by cancer cells to invariably re-buff our best-guess therapeutic advances. If one doesn’t guess, however, this road-block can be circumvented by systematically probing disease vs normal cells on a genome-wide (or in our case proteome-wide) scale for hyper-sensitive points of therapeutic intervention. Moreover, some of these sites may be uniquely sensitive to cancer cells given their heavy genomic re-wiring. This concept of ‘synthetic lethality’ is now being tried in a more determined way in recent times on KRAS. Our lead programme comprises one novel target in this area and Protein-i represents a systematic approach to mine for more synthetic lethal targets to KRAS, as well as other undruggable cancer genes in the future. Furthermore, we believe that cryptic druggable sites may also still exist in KRAS itself for targeting, which can likewise be uncovered by Protein-i and then converted to new drugs more effectively by the composite Site-Seeker platform.
JR: What will be the next steps in your program to develop a drug which can treat the “undruggable” cancer gene KRAS?
CT: Our longer term goal is to develop a therapeutic that can be given to cancer patients who specifically carry the KRAS gene mutation in their tumour DNA. The next major step of our efforts is to identify a single chemical substance, or drug, that is suitable to be provided to patients through hospitals that run clinical trials. We will confirm that our candidate drug is highly potent in the way we intend, has the minimal potential for side effects, and can be readily produced. Following review and acceptance by government regulators, the new medicine would then be manufactured as pills or IV bags, and distributed to doctors and the cancer patients they treat.
Before they could be provided to patients, the potential drug substances we have identified to-date have to undergo careful testing prior to industrial manufacture. These efforts are long and resource-intensive: Innovate UK funds will greatly accelerate and improve upon the investments we are making to develop a new potential medicine for the many cancer patients who are diagnosed with KRAS mutations, but lack effective treatment options.
For more information please visit - http://www.phoremost.com/