Proteome integral solubility alteration via label‐free DIA approach (PISA‐DIA), game changer in drug target deconvolution

Abstract Drug protein‐target identification in past decades required screening compound libraries against known proteins to determine drugs binding to specific protein. Protein targets used in drug‐target screening were selected predominantly used laborious genetic manipulation assays. In 2013, a team led by Pär Nordlund from Karolinska Institutet (Stockholm, Sweden) developed Cellular Thermal Shift Assay (CETSA), a method which, for the first time, enabled the possibility of drug protein‐target identification in the complex cellular proteome. High throughput, quantitative mass spectrometry (MS) proteomics appeared as a compatible analytical method of choice to complement CETSA, aka Thermal Protein Profiling assay (TPP). Since the seminal CETSA‐MS/ TPP‐MS publications, different protein‐target deconvolution strategies emerged including Proteome Integral Solubility Alteration (PISA). The work of Emery–Corbin et al. (Proteomics 2024, 2300644), titled Proteome Integral Solubility Alteration via label‐free DIA approach (PISA‐DIA), introduces Data–Independent Acquisition (DIA) as a quantification method, opening new avenues in drug target‐deconvolution field. Application of DIA for target deconvolution offers attractive alternative to widely used data dependent methodology.