"G-protein coupled receptors (GPCRs) are proteins found on the surface of cells: they detect molecules outside the cell and consequently activate internal signalling pathways that mediate cellular responses. GPCRs are one of the most important human drug target classes, and are addressed by 25-30% of marketed drugs. Many GPCRs that are known to have disease relevance remain undrugged, highlighting the ongoing importance of this target group in the search for new medicines. Historically, methods of studying GPCRs have been very successful at identifying and profiling chemicals that modulate their function. However, these empirical approaches have tended to find compounds that are only partially selective for the desired target, because they give insufficiently precise information to drive rational drug design towards highly-specific agents. Recently it has been shown that making mutated forms of some GPCRs makes them stable enough to use structural and biophysical methods that can allow the design of more selective drugs, and unlock traditionally undruggable targets of this class. But this is a difficult and lengthy task requiring extensive method development for each individual target. Domainex has embraced a new method for starting drug discovery projects using a biophysical technique called MicroScale Thermophoresis (MST). This proposal will test the feasibility of using this approach on GPCRs, in order to establish a generic platform that would enable work any purified GPCR without the need for stabilising mutations. We will use a new method developed in a UK university to stabilise the GPCR. If successful, this project will lead to a new service that Domainex can offer to prospective clients. This will provide the Company with new revenues, and facilitate our clients' research projects meaning that better drugs will get to patients, faster."

Our aim is to establish the feasibility of finding a new treatment for cancer by targeting a family of three enzymes called the NSDs. Recent academic research has shown that in myeloma and some other types of cancer the NSD family can switch on the production of other proteins that help these cancers grow. This work leads us to believe that a drug which can inactivate one or more of the NSDs could switch off these mechanisms and therefore have powerful anti-cancer effects, perhaps with few side-effects, because research suggests that in adult humans normally-growing cells may not need to use the NSD enzymes. This differentiates this approach from that of existing drugs, and of many other experimental treatments. This project will test this idea by finding compounds that can block NSDs, and finding out whether they have the expected effects on tumour cells and are safe to normal cells. If successful, this result will be the starting-point for a larger programme to find a potential drug that works in this way.

This project aims to deliver an advanced candidate drug for the treatment for Chronic Obstructive Pulmonary Disease (sometimes refered to as emphysema or chronic bronchitis) – a highly debilitating condition that affects more than 200 million people worldwide and leads to over 6 million early deaths every year. The consequent social, economic, and health-care burden is huge. Treatment for COPD usually involves relieving the symptoms, for example by using drugs delived through an inhaler, or supplementary oxygen, to make breathing easier. However the novel therapeutic mechanism that will be pioneered by this programme can be more conveniently taken as a tablet, rather than inhaled, and will target the processes that cause the disease, which should significantly slow - or even halt - its progression. These key aspects differentiates this approach from that of existing drugs, and of many other experimental treatments.

Our aim is to establish the feasibility of a new treatment for cancer that works by targeting the enzyme SMYD3. Recent academic research has shown that SMYD3 is not present in normal cells, but in many cancer cells it switches on the production of other proteins that help tumours grow and spread throughout the body. So this work suggests that a drug that inactivates SMYD3 will switch off these mechanisms, and have powerful anti-cancer properties, perhaps with few side-effects. This new mechanism would be very different than those of existing drugs, and of many other experimental treatments. This project will test this idea by identifying SMYD3-blocking compounds, and finding out whether they have the expected effects on tumour cells, and are safe to normal cells. If successful, this project will provide the starting-points for a larger programme to find a drug candidate that works in this way.

This project aims to establish the feasibility of a new treatment for Chronic Obstructive Pulmonary Disease – a highly debilitating condition that affects more than 200 million people worldwide and leads to over 6 million early deaths every year. The consequent social, economic, and health-care burden is huge. Treatment for COPD usually involves relieving the symptoms, for example by using drugs delived through an inhaler, or supplementary oxygen, to make breathing easier. However the novel therapeutic mechanism that will be pioneered by this programme will target the processes that cause the disease, which should significantly slow - or even halt - its progression. This key aspect differentiates this approach from that of existing drugs, and of many other experimental treatments.

Our aim is to invent a new drug for the treatment of several common cancers through inhibition of the enzymes IKKe and/or TBK1. Recent academic research has shown that blocking these closely-related protein kinases will stop cancer cells growing, and force them to die. Furthermore these enzymes are important in some inflamatory diseases, obesity, and Type 2 diabetes. Our initial markets are breast and ovarian cancers. Breast cancer is the most common cancer in women – every year it affects over a million women worldwide - and is the leading cause of death for women aged 40-44. The five-year survival rate for Stage V cancer patients (advanced disease progression) is just 16%. Ovarian cancer is rarely diagnosed in its early stages and is usually quite advanced by the time diagnosis is made, resulting in poor prognoses. The five-year survival rate for all stages is only 35% to 38%. An IKKe/TBK1 inhibitor would have a significant impact on patients with these cancers, leading to better quality of life, and improved five-year survival rates. This drug will also reduce healthcare costs because unlike many existing drugs, this new treatment will be designed to be taken as a pill at home, rather than by infusion in hospital. The objective of this programme is to identify a candidate drug that is effective in disease models and would be orally well-absorbed by humans. The subsequent commercialisation of this new drug would be through a partnership with a large pharmaceutical company with the resources to take on this expensive stage of product development. Domainex is presently a leader in this field. The funding of this proposal will allow Domainex to recruit a number of scientists – preserving highly-skilled drug discovery jobs in the UK. Given recent trends in the pharmaceutical industry it is very likely that the future of drug research in this country will be based largely upon the success and growth of biotechnology companies such as Domainex.

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