Standing on the shoulders of giants: a retrospective analysis of kinase drug discovery at AstraZeneca

•‘The most fruitful basis of the discovery of a new drug is to start with an old drug’.•Early projects had a profound influence on the kinase-focused discovery efforts that followed.•Kinase medicinal chemistry expertise has enabled optimisation strategies to be rapidly executed. Sir James Black famously said: ‘The most fruitful basis of the discovery of a new drug is to start with an old drug’, and this idea has featured in a significant number of kinase drug discovery programmes at AstraZeneca over the past two decades. Of the marketed kinase inhibitors and various clinically trialled agents, candidate drugs and multiple lead optimisation programmes delivered over this timeframe at AstraZeneca the overwhelming majority trace their origins back to a small handful of pioneering drug discovery programmes. Importantly, these projects not only laid the foundations of the organisational expertise on how to ‘drug’ this important target family but also provided a legacy of internal chemical equity that has had a profound influence on the many kinase-focused discovery efforts that have followed. For agents in late-stage clinical trials today, seemingly the product of rapid discovery phases, the reality is that these are often the products of decades of research. Crucial to the success of these projects has been the medicinal chemists involved, whose intimate knowledge and expertise around key kinase chemical scaffolds has enabled successful medicinal chemistry strategies to be rapidly identified and executed. In this article we reflect on two decades of kinase-focused drug discovery efforts within AstraZeneca and highlight the crucial role of the medicinal chemist in building the organisational knowledge around this important target family to drive increasingly more-efficient lead optimisation efforts.