NDD-derived assets: current self-funded programmes
We are currently focusing our internal resources on two self-funded NDD-derived immuno-oncology programmes. Click on the projects below to read more.
Hit to Lead
Tryptophan plays an important role in regulating immune tolerance, as demonstrated in the maintenance of the immune privilege of the placenta. The catabolism of tryptophan has been more recently revealed in tumours where it is purported to contribute towards immune evasion, with cancer cells suppressing T cell responses via both depletion of tryptophan and accumulation of its metabolite kynurenine. Project aim: To identify novel modulators of tryptophan catabolism with a distinct mechanism and superior pharmacological characteristics.
Immune checkpoint modulation
Immune checkpoints are part of the normal physiological 'braking system' of the immune response. Immune cell populations, such as T cells, carry receptors that transmit suppressive messages to the interior if they meet the appropriate external signal. In cancer, these signals can be generated inappropriately by tumour cells, thereby contributing to immune evasion by tumours. Project aim: To identify mechanistically novel small molecule modulators of immune checkpoint signalling that can be used in combination with existing treatments to improve patient responses; and in situations where patients do not respond to standard care.
Examples of partner-ready programmes
Our NDD platform can go from a biological concept to hits in months and has been validated across 12 diverse areas of biology. Positive data has been generated in the following programmes that are ready to be progressed to the next stage in collaboration with the right partner. Click on the projects below to read more.
Hit to Lead
Hedgehog pathway inhibition
The Hedgehog pathway is activated in cancers through deletions, mutations and changes in DNA methylation of multiple key components. Whilst initial pharmaceutical approaches have validated the pathway as a target, resistance is a frequent concern. Our NDD approach has identified novel inhibitors of tumour Hedgehog pathway activity that are active against cells that are resistant to the approved agent, demonstrate superior performance in vivo and appear to have a novel mechanism of action. Read more about this programme in the downloads section at the bottom of this page.
Tumour Necrosis Factor alpha is a master regulator of inflammation. Inhibition of the effects of TNF alpha is efficacious in the treatment of a number of inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, plaque psoriasis, Chrohn's disease and ulcerative colitis. Our NDD approach has yielded four chemically distinct lead series suitable for further medicinal chemistry optimisation. Read more about this programme in the downloads section at the bottom of this page.
Neurogenerative diseases, which include conditions such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease and amyotrophic lateral sclerosis, are characterised by irreversible, progressive dysfunction of the nervous system. Neurodegeneration is poorly served by existing drugs due to the complexity of the disease processes. Our NDD approach has successfully identified small molecules with neuroprotective activities. Read more about this programme in the downloads section at the bottom of this page.
Haemorrhage is a common adverse effect of anticoagulants. The aim of this programme is to identify a potent, broad spectrum small molecule potentiator of coagulation.
Vaccination is the main tool to minimise influenza infections, but requires surveillance of circulating strains and has limited effectivity. Our NDD approach has yielded two lead-series that are chemically different and have distinctive antiviral profiles - with one series active against influenza A and B strains and the other series lacking anti-influenza B activity. Read more about this programme in the downloads section at the bottom of this page.
Examples of projects in new areas
We have undertaken network analysis in the following commercially relevant areas offering an interesting potential for progressing asset discovery programmes with the right partner. Click on the projects below to read more.
Hit to Lead
Idiopathic pulmonary fibrosis (“IPF”)
Fibrosis, the excessive accumulation of fibrous connective tissue and extracellular matrix components, such as collagen and fibronectin, in and around inflamed or damaged tissue, is the final pathological outcome of most chronic inflammatory diseases. Idiopathic pulmonary fibrosis ("IPF") is a chronic, progressive disease of unknown aetiology that causes lung scarring. The disease prognosis is poor, with a median survival of 3-5 years after diagnosis. Estimated prevalence is c.20 people per 100,000 worldwide. Thereapeutic options are limited and the large unmet medical need in the field remains. Through our NDD approach, the use of omic data and network biology analysis could help to discover new drugs. Read more about this programme in the downloads section and the bottom of this page.
Innate immunity – STING
Only 20-40% of patients respond to immune checkpoint blockade ("ICB") therapy. The reason for this is believed to be related to the immuno-phenotype of the tumour microenvironment ("TME"). A T cell inflamed TME may be predictive of response to immunotherapies, as a high percentage of non-responders to ICB therapies have non-inflamed tumours. Our NDD approach could identify small molecules that could potentially convert a non-inflamed TME to an inflamed phenotype by elevating STING (stimulator of interferon genes). STING activation has been shown to enhance tumour regression where treatment with immune checkpoint inhibitors alone has not worked. Read more about this programme in the downloads section and the bottom of this page.
Tumour microenvironment - Macrophage polarisation
Tumour-associated macrophages ("TAMs") are the most abundant leukocytes in tumour stroma and derive from tissue-resident macrophages or from recruited inflammatory monocytes conditioned by the tumour microenvironment ("TME"). In tumour surroundings, stromal and tumour factors lead to an immunosuppresive TME that disrupts the tumoricidal function of macrophages. The application of our NDD approach, with omics data and network biology, could help to discover new drugs in an area of biological complexity. Read more about this programme in the downloads section and the bottom of this page.
Tumour microenvironment - T reg cell function
Regulatory T cells ("Tregs"), present throughout the body, are essential for the prevention of autoimmunity and for the maintenance of immune homeostasis. Tregs also play a pivotal role in inducing tumour-specific immune tolerance. Infiltration of tumours with high numbers of Tregs is often associated with poor clinical prognosis. Breaking down tumour-specific tolerance is a key step in the development of effective and durable cancer immunotherapy, with Tregs a key target. Our NDD approach may be used to identify small molecules that can attenuate intra-tumoral Treg functions and stability. Read more about this programme in the downloads section and the bottom of this page.
Neurodegeneration – Proteostasis
Neurodegenerative diseases are increasing in prevalence, with no curative therapies currently available. Many neurodegenerative diseases are characterised by the presence of disease-specific misfolded proteins. There have been a number of high profile failures of therapeutics targeting disease-specific misfolded proteins. Targeting processes occurring downstream of protein misfolding may be more rewarding than targeting individual aberrant proteins. Our NDD approach may be used to identify small molecules that can be tested for their effects on the unfolded protein response. Read more about this programme in the downloads section and the bottom of this page.