Beyond PAINs: Chemotype Sensitivity of Protein Methyltransferases in Screens

Screening of the relatively new target class, the lysine and arginine methyltransferases (MTases), presents unique challenges in the identification and confirmation of active chemical matter. Examination of high throughput screening data generated using Scintillation Proximity Assay (SPA) format for a number of protein MTase targets reveals sensitivity to both the known pan assay interference compounds (PAINS) and also other scaffolds not currently precedented as assay interferers. We find that, in general, true actives show significant selectivity within the MTase family. With the exception of slight modifications of SAM-like compounds, scaffolds that are observed frequently in multiple MTase assays should be viewed with caution and should be carefully validated before following up.