Different chemical proteomic approaches to identify the targets of lapatinib. (31st December 2023)

• Record Type: Journal Article
• Authors: Kovačević, Tatjana; Nujić, Krunoslav; Cindrić, Mario; Dragojević, Snježana; Vinter, Adrijana; Hozić, Amela; Mesić, Milan
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 38:Number 1(2023)
• Publication Date: 2023-12-31
• Subjects: Chemical proteomics -- affinity chromatography -- diazirines -- photoaffinity labelling -- EGFR -- lapatinib -- protein identification; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2023.2183809
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: The process of identifying the protein targets and off-targets of a biologically active compound is of great importance in modern drug discovery. Various chemical proteomics approaches have been established for this purpose. To compare the different approaches, and to understand which method would provide the best results, we have chosen the EGFR inhibitor lapatinib as an example molecule. Lapatinib derivatives were designed using linkers with motifs, including amino (amidation), alkyne (click chemistry) and the diazirine group (photo-affinity). These modified lapatinib analogues were validated for their ability to inhibit EGFR activity in vitro and were shown to pull down purified recombinant EGFR protein. In all of the approaches evaluated here, we identified EGFR as the main protein target from the lysate of immortalised cell line expressing EGFR, thus validating its potential use to identify unknown protein targets. Taken together, the results reported here give insight into the cellular activities of lapatinib.