AbbVie has been establishing itself as a key player in the phenotypic and virtual ligand screening space for many years. Shaun McLoughlin, Principal Research Scientist at AbbVie, explained that phenotypic screening requires examining libraries with great diversity and screening them against cellular models and other advanced pharmacologically relevant models. 

Within drug discovery, phenotypic screening is especially valuable when uncovering unexpected mechanisms and targets by moving beyond traditional target-based approaches and established guidelines. However, scientists may face the mental challenge of jettisoning their predispositions and assumptions about what is druggable and what isn’t, as well as the pathways relevant to pharmacology. 

McLoughlin presented an oncology vignette. He conducted a phenotypic screen in oncology and identified a compound that selectively kills oncogene addicted cancer cells. The main breakthrough came with the advent of CRISPR screening, which identified MGST1 as the key target. 

Tools like CETSA Classic were used to capture direct interactions. It was found that a thermal shift could be created on MGST1, which was then perturbed by adding the candidate, providing evidence of potential direct binding. McLoughlin was able to link MGST1 expression to compound sensitivity and reveal a novel mechanism involving lipid peroxidation and ferroptosis-like cell death.  Despite the high MGST1 expression in liver cells, the compound displayed a favourable therapeutic window in hepatocytes and zebrafish models. 

In a separate study in the neuroscience domain, McCloughlin and some collaborators from the Scripps Research Institute began investigating Tau aggregate clearance.  A phenotypic screen pinpointed a functionalised fragment of interest that appeared to clear Tau aggregates in neuronal cells.  He added that the compound showed promising Tau clearance in SH-SY5Y cells expressing mutant Tau.  

Structure-activity relationship optimisation led to a significant boost in potency. Furthermore, proteomics unveiled interactions with proteins containing selenocysteine or thioredoxin domains. P4HB was a prime example of this. These findings imply a mechanism linked to ER-based oxidation and aggregate clearance. Both case studies are ongoing, with Mcloughlin expressing that further work is needed to completely elucidate mechanisms and therapeutic applications.