Fragment-Based Drug Discovery approaches to tackle emerging multi-component therapeutic targets

Here we present recent work that has established a Fragment-Based Drug Discovery (FBDD) platform for the discovery of novel molecular glues, in this case between CRBN/DDB1 and RAS signalling pathway proteins: SOS1 and SHP2.  This validated SPR platform has shown initial success in glue discovery by identifying a novel candidate glue between CRBN/DDB1 and SHP2.

This showcases the utility of fragments as effective chemical starting points for glue discovery, and the use of SPR as a high-sensitivity, low-interference technology, ideal for application in this setting.  This platform, along with the Sygnature Fragment library and HTS collections, is ready for use against a wide range of target classes.

In recent years there has been an increasing effort to tackle more challenging therapeutic targets. This has been driven by a combination of better biological knowledge to identify targets for difficult-to-treat diseases, as well as existing successes with many of the more tractable targets. We have observed within our work that there has been a significant increase in drug targets that involve the interaction of two or more components, which can discover new therapeutic molecules complex and challenging.

Two key areas within this space include induced proximity therapeutics, such as bifunctional degraders and molecular glues, and the targeting of nucleic acid-binding proteins, such as helicases and polymerases. Whilst different, both types of target involve interactions beyond the one-to-one binding of a drug to a target, whether that is inducing the formation of a complex, or drugging an activation state that is only available in the presence of a binding partner, such as a nucleic acid. We believe that a biophysical approach using fragments is ideally suited to both applications (and more), to deliver medicinal chemistry starting points where other methods do not.