Development of autotaxin inhibitors as new treatment units in fibrosis and cancer

Respiratory diseases have a significant socio-economic impact in the UK, with direct costs to the economy of over £6 billion, notwithstanding the significant morbidity rate of 1 in 5 associated with such conditions. A disease that is increasingly prevalent is Idiopathic Pulmonary Fibrosis (IPF), and is characterised by fibrotic tissue in the lung. IPF has exceptionally high mortality, with a median survival rate of approximately 5 years (c.f. 6 years on average for cancer). Current estimates suggest that 5000 new cases present annually in the UK, with a 6-fold increase since 1979. Ovarian cancer is the second most common gynaecologic cancer and is the most deadly of these with 5-year survival rates ranging from <20-80%. This represents only a small increase in positive prognosis over the last 40 years. The enzyme Autotaxin is intimately involved in the pathology of both diseases and accordingly, the focus of this work is the identification of drug-like molecules which can potentially inhibit this system and lead to new treatment units for both these conditions. Previous efforts in this area have led to compounds with generally poor physical properties which are correlated with attrition in drug development. Based on our previous efforts, through the design and profiling of over 200 novel compounds, we have identified much higher quality starting points for further optimisation, delivering novel molecules with significantly improved physical properties. These promising leads, together with a comprehensive and enabling scientific network, spanning chemistry, physical property measurement, biochemistry and disease pharmacology mean we are well placed to be able to deliver higher quality drug candidates compared to progenitor compounds for this important therapeutic target.