Abstract

Choosing & Using Fragments in the Generation of Selective Kinase Inhibitors

Lee Walmsley, Senior Team Leader, Vernalis Ltd

There is often a debate about just how useful fragments are for well-established conventional targets such as protein kinases. Fragment screening however can be extremely valuable, providing critical ideas that lead to novelty, demonstrating how to achieve selectivity, helping dissect and make the most of HTS and literature compounds, alongside maximising ligand efficiency.Finding fragments that bind to such targets is straight-forward. For most kinases, a screen of our 1350 member fragment library results in between 40 to 170 validated and chemically distinct hits. In addition, crystal structures for these hits bound to the kinase can usually be obtained quite rapidly. The real challenge is how to digest all this information and decide how and which fragments to progress in order to identify the highest quality leads. My presentation will illustrate the approach taken at Vernalis in some recent projects which led to the discovery of novel lead series for a number of different kinases. The main messages are that: fragments always tell you something new about the binding site; careful triage and exploration of fragment SAR can give indications of how to achieve selectivity, novelty and affinity;it is important to optimise the fragment before investing large chemistry resources and that with patience, a fragment derived series will often supersede an HTS derived series and deliver a better quality of compound for lead optimisation.