Abstract

Astex Pharmaceuticals has been a pioneer of the Fragment-Based Drug Discovery (FBDD) platform and has successfully applied its proprietary approach to generate multiple new drug candidates that are progressing through clinical development. To date this has largely been in the oncology space but more recently we have moved into neuroscience and specifically neurodegeneration (i.e. FTD, ALS, PD, HD). Our approach is to first understand the molecular basis of the underlying disease pathophysiology and then to use this information to identify specific targets which are amenable to our technological focus. Mechanistic pathways of current interest include proteostasis, autophagy, mitochondrial quality control and neuroinflammation. In addition to our internal target validation capabilities, we are working extensively via Open Innovation networks and partnerships. The FBDD platform allows the identification of small fragments that bind to a protein structure and which can then serve as starting points for rationally designing (using structure led hypothesis testing) potency, selectivity and drug-like properties into lead molecules. Potentially this also permits us to control the physicochemical properties and molecular weight of compounds, increasing the chances of these ligands having brain penetration. The progress, successes, limitations and learnings of the Astex approach will be discussed.