The face of small molecule drug discovery is changing; the prevalence of enzymatically active targets with well-defined binding sites is diminishing in discovery portfolios. With the advent of functional genomics a plethora of novel targets has arisen in their place. Many of these fall under the broad description of challenging targets, a term capturing a number of different classes but all with the commonality they are hard to prosecute via traditional screening methods. Many are catalytically inert, operate via protein-protein interactions and can be intrinsically disordered. To tackle these targets new therapeutic modalities have arisen such as PROTACs and molecular glues. The screening paradigm has necessarily needed to evolve along with these changes. Here we describe our experiences with Affinity Selection Mass Spectrometry (AS-MS) to drive rapid hit discovery and facilitate working with challenging targets. We’ll discuss how our process has evolved, the challenges we’ve faced along with the strengths and limitations of the approach. Finally we’ll talk about where we wish to go in the future.
