New synthetic chemistry fuelling new drug discovery paradigms

The extraordinary and unsustainable cost of new medications is a direct effect of high attrition rates in drug discovery (>99%). This failure rate is an inherent feature of contemporary target-led approaches to drug discovery that rely upon a hypothetical small-molecule / biomolecule (target) interaction. This hypothesis is only testable after extensive and expensive compound screening and medicinal chemistry optimisation for the purposes of undertaking proof-of-concept (PoC) studies, initially in cells and then in animal models (see box). The success rate of these preclinical PoC studies is < 10% and of these successes < 5% succeed in human clinical trials.

Our group is focused on addressing this using the emerging paradigm of phenotypic drug discovery (PDD)
1. PDD has lower discovery costs and is giving a higher success rates than target-led approaches
2. A key bottle-neck to PDD is gaining suitable access to the most effective chemotypes for phenotypic screening.

Our work is directed at addressing this by developing efficient synthetic access to privileged multi-stereocentre containing chemotypes including natural products and natural product-like scaffolds (eg 1-3) and to biased libraries that exhibit high preference for specific biochemical pathways implicated in disease (eg 4). This approach is proving very productive with recent PDD successes from our labs including two successful clinical candidates (cancer and anxiety) [1] and emerging therapies or autoimmune disease and cancer.