Discovery of Novel Ligase Ligands Using Affinity Selection Mass Spectrometry

Affinity selection mass spectrometry (ASMS) is a label-free binding method that enables the identification of novel ligands for drug discovery. Since ASMS is agnostic of the binding mechanism, it is ideally suited to discovering ligands for targeted protein degradation (TPD).

We performed a screen of our LeadFinder library of 150K lead-like compounds to identify compounds binding to the VHL complex, VCB, that could serve as starting points for TPD programmes. Using our 2DLC-TOF system we performed an online size exclusion chromatography (SEC) ASMS method based on the automated ligand identification system (ALIS).

We identified novel binders from the pooled screen, subsequently confirmed in an ASMS retest of singletons. This work highlights the potential of ASMS in advancing drug discovery efforts, particularly for TPD applications, by providing a reliable and efficient approach to discovering high-affinity ligands.